CN101389770A - 用于诊断和治疗实体癌的基于微小rna的方法和组合物 - Google Patents
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Abstract
本发明提供了用于诊断和治疗实体癌的新的方法和组合物。本发明也提供了鉴定肿瘤发生抑制剂的方法。
Description
发明人:Carlo M.Croce,George A.Calin和Stefano Volinia
政府资助
本发明全部或部分由来自国立癌症研究所的项目基金P01CA76259,P01CA81534和P30CA56036资助。政府具有本发明的某些权利。
发明背景
癌症(恶性细胞的不受控生长)是现代医学纪元的一个主要健康问题,也是发达国家主导死因之一。在美国,四分之一的死亡由癌症造成(Jemal,A.等人,CA Cancer J.Clin.52:23-47(2002))。在癌症中,称作实体癌的源自器官和实体组织的癌症(例如结肠癌,肺癌,乳腺癌,胃癌,前列腺癌,胰腺癌)属于最常鉴定的人癌症。
例如,前列腺癌是工业化国家男性中最常诊断出的非皮肤恶性肿瘤,在美国,八名男性中有一名会在他的生命中发生前列腺癌(Simard,J.等人,Endocrinology 143(6):2029-40(2002))。在最近的数十年中,前列腺癌的发病率已经急剧增加,前列腺癌现在是美国和西欧的主导死因(Peschel,R.E.和J.W.Colberg,Lancet4:233-41(2003);Neson,W.G.等人,N.Engl.J.Med.349(4):366-81(2003))。具有前列腺癌的男性的寿命预期平均减少了40%。如果在转移和局部扩散超过包膜之前早期检测到,前列腺癌经常可以治愈(例如使用手术)。但是,如果在从前列腺扩散和转移后诊断出来,前列腺癌通常是具有低治愈率的致命疾病。尽管基于前列腺特异性抗原(PSA)的筛选已经辅助前列腺癌的早期诊断,它既不是高灵敏度的,也不是特异性的(Punglia等人,N.Engl.J.Med.349(4):335-42(2003))。这意味着,该测试伴随着高百分比的假阴性和假阳性诊断。结果是许多情况下癌症被漏诊和对没有癌症的那些人的不必要的随访活检。
乳腺癌仍然是妇女中癌症相关性死亡的第二大病因,在美国其每年影响着超过180,000名妇女。对于北美的妇女,一生中患乳腺癌的概率现在为八分之一。尽管BRCA1和BRCA2的发现在鉴定参与乳腺癌的关键遗传因素中是非常重要的步骤,但已逐渐清楚BRCA1和BRCA2的突变只解释部分对乳腺癌的遗传易感性(Nathanson,K.L.,等人,Human Mol.Gen.10(7):715-720(2001);Anglican Breast CancerStudy Group.Br.J.Cancer 83(10):1301-08(2000);和Syrjakoski,K.,等人,J.Natl.Cancer Inst.92:1529-31(2000))。尽管对乳腺癌的治疗进行了大量研究,但乳腺癌仍然难以有效地诊断和治疗,并且在乳腺癌患者中观察到的高死亡率表明该疾病的诊断、治疗和预防需要改进。
除外皮肤癌,结肠直肠癌是在美国和加拿大第三最常诊断出的癌症(在女性中,位于肺癌和乳腺癌之后,在男性中,位于肺癌和前列腺癌之后)。美国癌症学会估计,在2005年美国将有约145,000例新诊断出的的结肠直肠癌病例(Cancer Facts and Figures 2005.Atlanta,GA:American Cancer Society,2005.可从www.cancer.org/docroot/STT/stt_0.asp获得,2005年12月19日访问)。结肠直肠癌是美国和加拿大男性和女性癌症死亡的第二大原因(次于肺癌)。
2004年美国胰腺癌的年发病率几乎等同于年死亡率,分别估计为31,860和31,270(Cancer Facts and Figures 2004.Atlanta,GA:American Cancer Society,2004.可从www.cancer.org/docroot/STT/stt_0_2004.asp获得,2005年8月21日访问)。具有局部进展和转移性胰腺癌的患者具有较差的预后,诊断通常对于治疗性手术或放疗而言发生得太迟(Burr,H.A.,等人,The Oncologist 10(3):183-190,(2005))。化疗可以为有些晚期胰腺癌患者提供症状的缓解,但是迄今为止它对存活率的影响不大。
在美国,每年有超过20,000人被诊断出胃癌。美国癌症学会估计,在2004年美国将有22,710例新诊断出的的胃癌病例(Cancer Factsand Figures 2004.Atlanta,GA:American Cancer Society,2004.可从www.cancer.org/docroot/STT/stt_0_2004.asp获得,2005年8月21日访问)。因为胃癌可以无症状地发生,到诊断作出时其可能已经是晚期。那时治疗旨在使患者更舒服和提高生命质量。
在世界范围内,肺癌造成比任何其它形式的癌症更多的死亡(Goodman,G.E.,Thorax 57:994-999(2002))。在美国,肺癌是男性和女性癌症死亡的主要原因。在2002年,肺癌死亡率估计是134,900例,超过乳腺癌、前列腺癌和结肠癌的总和。相同出处。肺癌也是所有欧洲国家癌症死亡的主要原因,肺癌-相关死亡的数目在发展中国家也快速增加。
无论在诊断时的疾病阶段,所有肺癌患者的五年生存率仅是约13%。这与在该疾病仍然在局部时检测出的病例的46%的五年生存率形成对比。但是,在该疾病已经扩散之前,仅16%的肺癌被发现。早期检测是困难的,因为在该疾病已经达到晚期之前经常观察不到临床症状。尽管对该癌症和其它癌症的治疗进行了研究,肺癌仍然难以有效地诊断和治疗。
显然,负责对特定形式的实体癌(例如前列腺癌,乳腺癌,肺癌,胃癌,结肠癌,胰腺癌)的易感性的标记和基因的鉴定,是今天肿瘤学面临的主要挑战之一。需要鉴定早期检测具有对癌症的遗传易感性的个体的方法,以便可以为癌症的早期检测和治疗制定更有力的筛选和干预方案。癌基因也可以揭示可以被操纵的关键分子途径(例如使用小或大分子量药物),且可以导致更有效的治疗,无论在首次诊断出特定癌症时的癌症阶段。
微小RNA是通过与信使RNA(mRNA)靶杂交并引发对它的翻译抑制或较不常见地引起其降解来控制基因表达的一类小的非编码RNA。miRNA的发现和研究已揭示在生物发育和各种细胞过程例如细胞分化、细胞生长和细胞死亡中发挥重要作用的miRNA介导的基因调控机制(Cheng,A.M.,等人,Nucleic Acids Res.33:1290-1297(2005))。近年来的研究表明,特定miRNA的异常表达可参与人的疾病,例如神经障碍(Ishizuka,A.,等人,Genes Dev.16:2497-2508(2002))和癌症。具体地,已在人慢性淋巴细胞性白血病中发现miR-16-1和/或miR-15a的不当表达(Calin,G.A.,等人,Proc.Natl.Acad.Sci.U.S.A.99:15524-15529(2002))。
显然,本领域非常需要改进的检测和治疗实体癌(例如前列腺癌,乳腺癌,肺癌,胃癌,结肠癌,胰腺癌)的方法。本发明提供了用于诊断和治疗实体癌的新的方法和组合物。
发明概述
本发明部分地基于在特定实体癌中具有改变的表达水平的特定miRNA的鉴定。
因此,本发明包括诊断受试者是否患有实体癌或处于发生实体癌的风险中的方法。根据本发明的方法,将受试者的测试样品中至少一种miR基因产物的水平与对照样品中的相应的miR基因产物的水平相比较。与对照样品中相应的miR基因产物的水平相比,测试样品中所述miR基因产物的水平的改变(例如增加,降低),指示着受试者患有实体癌或处于发生实体癌的风险中。所述实体癌可以是源自器官和实体组织的任意癌症。在某些实施方案中,所述实体癌是胃癌,乳腺癌,胰腺癌,结肠癌,肺癌或前列腺癌。在具体实施方案中,所述实体癌不是乳腺癌,肺癌,前列腺癌,胰腺癌或胃肠癌。
在一个实施方案中,在测试样品中测量的至少一种miR基因产物选自:miR-21,miR-191,miR-17-5p和其组合。在另一个实施方案中,在测试样品中测量的至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
在一个实施方案中,所述实体癌是乳腺癌或肺癌,且在测试样品中测量的至少一种miR基因产物选自:miR-210,miR-213和其组合。
在另一个实施方案中,所述实体癌是结肠癌,胃癌,前列腺癌或胰腺癌,且在测试样品中测量的至少一种miR基因产物是miR-218-2。
在一个特定实施方案中,所述实体癌是乳腺癌,且在测试样品中测量的至少一种miR基因产物选自:miR-125b-1,miR-125b-2,miR-145,miR-21和其组合。在一个相关实施方案中,所述实体癌是乳腺癌,且测试样品中的至少一种miR基因产物选自:miR-21,miR-29b-2,miR-146,miR-125b-2,miR-125b-1,miR-10b,miR-145,miR-181a,miR-140,miR-213,miR-29a prec,miR-181b-1,miR-199b,miR-29b-1,miR-130a,miR-155,let-7a-2,miR-205,miR-29c,miR-224,miR-100,miR-31,miR-30c,miR-17-5p,miR-210,miR-122a,miR-16-2和其组合。
在另一个实施方案中,所述实体癌是结肠癌,且测试样品中的至少一种miR基因产物选自:miR-24-1,miR-29b-2,miR-20a,miR-10a,miR-32,miR-203,miR-106a,miR-17-5p,miR-30c,miR-223,miR-126*,miR-128b,miR-21,miR-24-2,miR-99b prec,miR-155,miR-213,miR-150,miR-107,miR-191,miR-221,miR-9-3和其组合。
在另一个实施方案中,所述实体癌是肺癌,且测试样品中的miR基因产物选自:miR-21,miR-205,miR-200b,miR-9-1,miR-210,miR-148,miR-141,miR-132,miR-215,miR-128b,let-7g,miR-16-2,miR-129-1/2prec,miR-126*,miR-142-as,miR-30d,miR-30a-5p,miR-7-2,miR-199a-1,miR-127,miR-34a prec,miR-34a,miR-136,miR-202,miR-196-2,miR-199a-2,let-7a-2,miR-124a-1,miR-149,miR-17-5p,miR-196-1prec,miR-10a,miR-99b prec,miR-196-1,miR-199b,miR-191,miR-195,miR-155和其组合。
在另一个实施方案中,所述实体癌是胰腺癌,且在测试样品中测量的至少一种miR基因产物选自:miR-103-1,miR-103-2,miR-155,miR-204和其组合。在一个相关实施方案中,所述实体癌是胰腺癌,且测试样品中的miR基因产物选自:miR-103-2,miR-103-1,miR-24-2,miR-107,miR-100,miR-125b-2,miR-125b-1,miR-24-1,miR-191,miR-23a,miR-26a-1,miR-125a,miR-130a,miR-26b,miR-145,miR-221,miR-126*,miR-16-2,miR-146,miR-214,miR-99b,miR-128b,miR-155,miR-29b-2,miR-29a,miR-25,miR-16-1,miR-99a,miR-224,miR-30d,miR-92-2,miR-199a-1,miR-223,miR-29c,miR-30b,miR-129-1/2,miR-197,miR-17-5p,miR-30c,miR-7-1,miR-93-1,miR-140,miR-30a-5p,miR-132,miR-181b-1,miR-152prec,miR-23b,miR-20a,miR-222,miR-27a,miR-92-1,miR-21,miR-129-1/2prec,miR-150,miR-32,miR-106a,miR-29b-1和其组合。
在另一个实施方案中,所述实体癌是前列腺癌,且测试样品中的miR基因产物选自:let-7d,miR-128a prec,miR-195,miR-203,let-7a-2prec,miR-34a,miR-20a,miR-218-2,miR-29a,miR-25,miR-95,miR-197,miR-135-2,miR-187,miR-196-1,miR-148,miR-191,miR-21,let-7i,miR-198,miR-199a-2,miR-30c,miR-17-5p,miR-92-2,miR-146,miR-181b-1prec,miR-32,miR-206,miR-184prec,miR-29a prec,miR-29b-2,miR-149,miR-181b-1,miR-196-1prec,miR-93-1,miR-223,miR-16-1,miR-101-1,miR-124a-1,miR-26a-1,miR-214,miR-27a,miR-24-1,miR-106a,miR-199a-1和其组合。
在另一个实施方案中,所述实体癌是胃癌,且测试样品中的miR基因产物选自:miR-223,miR-21,miR-218-2,miR-103-2,miR-92-2,miR-25,miR-136,miR-191,miR-221,miR-125b-2,miR-103-1,miR-214,miR-222,miR-212prec,miR-125b-1,miR-100,miR-107,miR-92-1,miR-96,miR-192,miR-23a,miR-215,miR-7-2,miR-138-2,miR-24-1,miR-99b,miR-33b,miR-24-2和其组合。
使用本领域技术人员众所周知的众多技术(例如,定量或半定量RT-PCR,RNA印迹分析,溶液杂交检测),可以测量至少一种miR基因产物的水平。在一个具体的实施方案中,如下测量至少一种miR基因产物的水平:从获自受试者的测试样品逆转录RNA,以提供一组靶寡脱氧核苷酸,使所述靶寡脱氧核苷酸与一种或多种miRNA-特异性探针寡核苷酸杂交(例如,与包含几种miRNA-特异性探针寡核苷酸的微阵列杂交),以提供测试样品的杂交谱,并对比测试样品杂交谱与从对照样品产生的杂交谱。测试样品中至少一种miRNA的信号相对于对照样品的变化指示着受试者患有实体癌或处于发生实体癌的风险中。在一个特定实施方案中,使靶寡核苷酸与包含针对选自下述的一种或多种miRNA的miRNA-特异性探针寡核苷酸的微阵列杂交:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
本发明也包括抑制患有或被怀疑患有实体癌(例如前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌,结肠癌)的受试者的肿瘤发生的方法,其中受试者癌细胞中的至少一种miR基因产物失调(例如,减量调节,增量调节)。当至少一种分离的miR基因产物在癌细胞中减量调节时,该方法包括,施用有效量的分离的miR基因产物、分离的变体或miR基因产物或变体的生物活性片段,从而抑制受试者中癌细胞的增殖。在另一个实施方案中,所述至少一种分离的miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。在一个特定的实施方案中,所述miR基因产物不是miR-15a或miR-16-1。当至少一种分离的miR基因产物在癌细胞中增量调节时,该方法包括,给受试者施用有效量的至少一种用于抑制所述至少一种miR基因产物的表达的化合物(在本文中称作"抑制miR表达的化合物"),从而抑制受试者中癌细胞的增殖。在一个特定的实施方案中,所述至少一种抑制miR表达的化合物对选自下述的miR基因产物是特异性的:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
在一个相关实施方案中,抑制受试者中肿瘤发生的方法另外包括下述步骤:测定受试者癌细胞中至少一种miR基因产物的量,并将细胞中miR基因产物的水平与对照细胞中相应的miR基因产物的水平相对比。如果癌细胞中miR基因产物的表达失调(例如,减量调节,增量调节),该方法另外包括,改变在癌细胞中表达的所述至少一种miR基因产物的量。在一个实施方案中,在癌细胞中表达的miR基因产物的量小于在对照细胞(例如多个对照细胞)中表达的miR基因产物的量,并将有效量的减量调节的miR基因产物、分离的变体或miR基因产物或变体的生物活性片段施用给受试者。适用于该实施方案的miR基因产物包括miR-145,miR-155,miR-218-2和其组合,以及其它。在一个特定的实施方案中,所述miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,在癌细胞中表达的miR基因产物的量大于在对照细胞(例如多个对照细胞)中表达的miR基因产物的量,并将有效量的至少一种用于抑制所述至少一种增量调节的miR基因产物的表达的化合物施用给受试者。适用于抑制所述至少一种miR基因产物的表达的化合物包括、但不限于,抑制miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合的表达的化合物。
本发明另外提供了用于治疗实体癌(例如前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌,结肠癌)的药物组合物。在一个实施方案中,所述药物组合物包含至少一种分离的miR基因产物和药学上可接受的载体。在一个特定的实施方案中,所述至少一种miR基因产物对应于在癌细胞中的表达水平比在对照细胞中降低的miR基因产物。在某些实施方案中,所述分离的miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
在另一个实施方案中,本发明的药物组合物包含至少一种抑制miR表达的化合物和药学上可接受的载体。在一个特定的实施方案中,所述至少一种抑制miR表达的化合物对在癌细胞中的表达大于在对照细胞中的表达的miR基因产物是特异性的。在某些实施方案中,所述抑制miR表达的化合物对选自下述的一种或多种miR基因产物是特异性的:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
本发明也包括鉴定肿瘤发生抑制剂的方法,其包括给细胞提供测试试剂,和测量细胞中至少一种miR基因产物的水平。在一个实施方案中,该方法包括,给细胞提供测试试剂,和测量与实体癌(例如前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌,结肠癌)中降低的表达水平有关的至少一种miR基因产物的水平。与合适的对照细胞相比,所述细胞中所述miR基因产物的水平的增加,指示着测试试剂是肿瘤发生抑制剂。在一个特定的实施方案中,所述与实体癌细胞中降低的表达水平有关的至少一种miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
在其它实施方案中,该方法包括,给细胞提供测试试剂,和测量与实体癌中增加的表达水平有关的至少一种miR基因产物的水平。与合适的对照细胞相比,所述细胞中所述miR基因产物的水平的降低,指示着测试试剂是肿瘤发生抑制剂。在一个特定的实施方案中,所述与实体癌细胞中增加的表达水平有关的至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
附图简述
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图1描述了代表6种实体癌(顶部)和相应的正常组织的540个样品的聚类分析。在树中包括的miRNA(n=137)代表着其表达水平(减去背景的强度)高于至少50%的分析样品中的阈值(256)的那些。阵列以中位值为中心,并使用Gene Cluster 2.0标准化。使用非中心化的关联度量,进行平均关联聚类。颜色指示着每个样品中的微小RNA的表达水平与中位值的差异。
图2描述了微小RNA表达数据的非监督分析。过滤涵盖乳腺、结肠、肺、胰腺、前列腺和胃(正常组织和肿瘤)的540个样品(在图顶部标明)的微小RNA谱,定中心,并对每个特征标准化。在样品(水平方向)和特征(垂直方向)上对数据进行分级聚类,以平均关联和皮尔森关联作为相似性度量。样品名称指示在图的顶部,miRNA名称在左侧。探针ID指示在括号中,因为相同的微小RNA可以用不同的寡核苷酸测量。颜色指示着每个样品中的微小RNA的表达水平与中位值的差异。
图3描述了实体癌(顶部)之间差异调节的miRNA的表达。代表了在至少90%的组织实体癌中存在的61种微小RNA(图右侧)。树显示了在log2转化后每个列出的微小RNA的平均绝对表达值。对来自相同组织或肿瘤组织型的所有样品,计算平均值。以基因的平均值为中心,并使用Gene Cluster 2.0标准化。使用欧几里德距离法,进行平均关联聚类。
图4描述了在至少75%的实体瘤中存在的miRNA的表达的倍数变化,其中与正常样品相比,在不同癌样品(顶部)中的至少1个肿瘤绝对值高于2。树显示了平均倍数变化(癌症相对于正常)的log2转化。对来自相同组织或肿瘤组织型的所有样品,计算平均值。以阵列的平均值为中心,并使用Gene Cluster 2.0标准化。使用非中心化的关联度量,进行平均关联聚类。
图5描述了在至少50%的实体瘤的特征中存在的miRNA的表达的倍数变化(癌症相对于正常样品)。树显示了平均倍数变化(癌症相对于正常)的log2转化。对来自相同组织或肿瘤组织型的所有样品,计算平均值。以阵列的平均值为中心,并使用Gene Cluster 2.0标准化。使用非中心化的关联度量,进行平均关联聚类。
图6A描述的条形图指示了编码癌蛋白的不同基因的3’UTR使得能通过微小RNA实现癌调节。将萤火虫萤光素酶表达的相对阻遏(倍数变化)相对于花虫萤光素酶对照标准化。PLAG1,多形腺瘤基因1;TGFBR2,转化生长因子β受体II;Rb,视网膜母细胞瘤基因。pGL-3(Promega)用作空载体。miR-20a,miR-26a-1和miR-106寡RNA(有义,混杂)用于转染。在下图中显示了使用每个靶mRNA的突变版本(其缺少5’miRNA-末端互补位点(MUT))作为对照的第二个实验。所有实验一式三份地进行2遍(n=6)。
图6B描述的蛋白印迹表明,在某些癌症(例如肺癌,乳腺癌,结肠癌,胃癌)中,RB1(Rb)蛋白的水平表现出与miR-106a表达水平的负相关。β-肌动蛋白用作标准化的对照。N1,正常样品;T1和T2,肿瘤样品。
图7描述的RNA印迹显示了与正常样品相比乳腺癌样品(P系列和编号系列)中miR-145的减量调节(顶部)和miR-21表达的增量调节(底部)。用U6-特异性的探针进行标准化。
图8描述的RNA印迹显示了与正常样品(K系列)相比,不同内分泌胰腺癌样品(WDET,分化良好的胰腺内分泌肿瘤,WDEC,分化良好的胰腺内分泌癌,和ACC,胰腺腺泡细胞癌)中miR-103的增量调节和miR-155的减量调节(顶部)表达,以及与正常样品(K系列)和不分泌的/无功能的(NF-系列)样品相比,胰岛素瘤(F系列)中miR-204(底部)表达的增量调节。使用对5S RNA特异性的探针,进行标准化。
发明详述
本发明部分地基于,与正常的对照细胞相比,在与不同实体癌如结肠癌、胃癌、胰腺癌、肺癌、乳腺癌和前列腺癌有关的癌细胞中的表达发生改变的特定miRNA的鉴定。
如本文中互换使用的,"miR基因产物,""微小RNA,""miR,"或"miRNA"是指来自miR基因的未加工的(例如前体)或加工过的(例如成熟的)RNA转录物。由于miR基因产物不翻译成蛋白,术语"miR基因产物"不包括蛋白。未加工的miR基因转录物也称作"miR前体"或"miRprec",通常包含长度为约70-100个核苷酸的RNA转录物。miR前体可以用RNA酶(例如,Dicer,Argonaut,或RNA酶III(例如,大肠杆菌RNA酶III))消化加工成有活性的19-25个核苷酸的RNA分子。该有活性的19-25个核苷酸的RNA分子也称作"加工过的"miR基因产物或"成熟的"miRNA。
所述有活性的19-25个核苷酸的RNA分子可以通过天然加工途径(例如,使用完整细胞或细胞裂解物)或通过合成加工途径(例如,使用分离的加工酶,例如分离的Dicer,Argonaut,或RNA酶III)从miR前体得到。应当理解,所述有活性的19-25个核苷酸的RNA分子也可以通过生物或化学合成直接生成,不从miR前体加工。当在本文中用名称提及微小RNA时,该名称对应着前体和成熟形式两者,除非另有说明。
表1a和1b描述了特定的前体和成熟人微小RNA的核苷酸序列。
表1a-人微小RNA前体序列
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
let-7a-1 | CACUGUGGGAUGAGGUAGUAGGUUGUAUAGUUUUAGGGUCACACCCACCACUGGGAGAUAACUAUACAAUCUACUGUCUUUCCUAACGUG | 1 |
let-7a-2 | AGGUUGAGGUAGUAGGUUGUAUAGUUUAGAAUUACAUCAAGGGAGAUAACUGUACAGCCUCCUAGCUUUCCU | 2 |
let-7a-3 | GGGUGAGGUAGUAGGUUGUAUAGUUUGGGGCUCUGCCCUGCUAUGGGAUAACUAUACAAUCUACUGUCUUUCCU | 3 |
let-7a-4 | GUGACUGCAUGCUCCCAGGUUGAGGUAGUAGGUUGUAUAGUUUAGAAUUACACAAGGGAGAUAACUGUACAGCCUCCUAGCUUUCCUUGGGUCUUGCACUAAACAAC | 4 |
let-7b | GGCGGGGUGAGGUAGUAGGUUGUGUGGUUUCAGGGCAGUGAUGUUGCCCCUCGGAAGAUAACUAUACAACCUACUGCCUUCCCUG | 5 |
let-7c | GCAUCCGGGUUGAGGUAGUAGGUUGUAUGGUUUAGAGUUACACCCUGGGAGUUAACUGUACAACCUUCUAGCUUUCCUUGGAGC | 6 |
let-7d | CCUAGGAAGAGGUAGUAGGUUGCAUAGUUUUAGGGCAGGGAUUUUGCCCACAAGGAGGUAACUAUACGACCUGCUGCCUUUCUUAGG | 7 |
let-7d-v1 | CUAGGAAGAGGUAGUAGUUUGCAUAGUUUUAGGGCAAAGAUUUUGCCCACAAGUAGUUAGCUAUACGACCUGCAGCCUUUUGUAG | 8 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
let-7d-v2 | CUGGCUGAGGUAGUAGUUUGUGCUGUUGGUCGGGUUGUGACAUUGCCCGCUGUGGAGAUAACUGCGCAAGCUACUGCCUUGCUAG | 9 |
let-7e | CCCGGGCUGAGGUAGGAGGUUGUAUAGUUGAGGAGGACACCCAAGGAGAUCACUAUACGGCCUCCUAGCUUUCCCCAGG | 10 |
let-7f-1 | UCAGAGUGAGGUAGUAGAUUGUAUAGUUGUGGGGUAGUGAUUUUACCCUGUUCAGGAGAUAACUAUACAAUCUAUUGCCUUCCCUGA | 11 |
let-7f-2-1 | CUGUGGGAUGAGGUAGUAGAUUGUAUAGUUGUGGGGUAGUGAUUUUACCCUGUUCAGGAGAUAACUAUACAAUCUAUUGCCUUCCCUGA | 12 |
let-7f-2-2 | CUGUGGGAUGAGGUAGUAGAUUGUAUAGUUUUAGGGUCAUACCCCAUCUUGGAGAUAACUAUACAGUCUACUGUCUUUCCCACGG | 13 |
let-7g | UUGCCUGAUUCCAGGCUGAGGUAGUAGUUUGUACAGUUUGAGGGUCUAUGAUACCACCCGGUACAGGAGAUAACUGUACAGGCCACUGCCUUGCCAGGAACAGCGCGC | 14 |
let-7i | CUGGCUGAGGUAGUAGUUUGUGCUGUUGGUCGGGUUGUGACAUUGCCCGCUGUGGAGAUAACUGCGCAAGCUACUGCCUUGCUAG | 15 |
miR-1b-1-1 | ACCUACUCAGAGUACAUACUUCUUUAUGUACCCAUAUGAACAUACAAUGCUAUGGAAUGUAAAGAAGUAUGUAUUUUUGGUAGGC | 16 |
miR-1b-1-2 | CAGCUAACAACUUAGUAAUACCUACUCAGAGUACAUACUUCUUUAUGUACCCAUAUGAACAUACAAUGCUAUGGAAUGUAAAGAAGUAUGUAUUUUUGGUAGGCAAUA | 17 |
miR-1b-2 | GCCUGCUUGGGAAACAUACUUCUUUAUAUGCCCAUAUGGACCUGCUAAGCUAUGGAAUGUAAAGAAGUAUGUAUCUCAGGCCGGG | 18 |
miR-1b | UGGGAAACAUACUUCUUUAUAUGCCCAUAUGGACCUGCUAAGCUAUGGAA UGUAAAGAAGUAUGUAUCUCA | 19 |
miR-1d | ACCUACUCAGAGUACAUACUUCUUUAUGUACCCAUAUGAACAUACAAUGCUAUGGAAUGUAAAGAAGUAUGUAUUUUUGGUAGGC | 20 |
miR-7-1a | UGGAUGUUGGCCUAGUUCUGUGUGGAAGACUAGUGAUUUUGUUGUUUUUAGAUAACUAAAUCGACAACAAAUCACAGUCUGCCAUAUGGCACAGGCCAUGCCUCUACA | 21 |
miR-7-1b | UUGGAUGUUGGCCUAGUUCUGUGUGGAAGACUAGUGAUUUUGUUGUUUUUAGAUAACUAAAUCGACAACAAAUCACAGUCUGCCAUAUGGCACAGGCCAUGCCUCUACAG | 22 |
miR-7-2 | CUGGAUACAGAGUGGACCGGCUGGCCCCAUCUGGAAGACUAGUGAUUUUG UUGUUGUCUUACUGCGCUCAACAACAAAUCCCAGUCUACCUAAUGGUGCCAGCCAUCGCA | 23 |
miR-7-3 | AGAUUAGAGUGGCUGUGGUCUAGUGCUGUGUGGAAGACUAGUGAUUUUGU UGUUCUGAUGUACUACGACAACAAGUCACAGCCGGCCUCAUAGCGCAGACUCCCUUCGAC | 24 |
miR-9-1 | CGGGGUUGGUUGUUAUCUUUGGUUAUCUAGCUGUAUGAGUGGUGUGGAGUCUUCAUAAAGCUAGAUAACCGAAAGUAAAAAUAACCCCA | 25 |
miR-9-2 | GGAAGCGAGUUGUUAUCUUUGGUUAUCUAGCUGUAUGAGUGUAUUGGUCUUCAUAAAGCUAGAUAACCGAAAGUAAAAACUCCUUCA | 26 |
miR-9-3 | GGAGGCCCGUUUCUCUCUUUGGUUAUCUAGCUGUAUGAGUGCCACAGAGCCGUCAUAAAGCUAGAUAACCGAAAGUAGAAAUGAUUCUCA | 27 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-10a | GAUCUGUCUGUCUUCUGUAUAUACCCUGUAGAUCCGAAUUUGUGUAAGGAAUUUUGUGGUCACAAAUUCGUAUCUAGGGGAAUAUGUAGUUGACAUAAACACUCCGCUCU | 28 |
miR-10b | CCAGAGGUUGUAACGUUGUCUAUAUAUACCCUGUAGAACCGAAUUUGUGUGGUAUCCGUAUAGUCACAGAUUCGAUUCUAGGGGAAUAUAUGGUCGAUGCAAAAACUUCA | 29 |
miR-15a-2 | GCGCGAAUGUGUGUUUAAAAAAAAUAAAACCUUGGAGUAAAGUAGCAGCA CAUAAUGGUUUGUGGAUUUUGAAAAGGUGCAGGCCAUAUUGUGCUGCCUCAAAAAUAC | 30 |
miR-15a | CCUUGGAGUAAAGUAGCAGCACAUAAUGGUUUGUGGAUUUUGAAAAGGUGCAGGCCAUAUUGUGCUGCCUCAAAAAUACAAGG | 31 |
miR-15b-1 | CUGUAGCAGCACAUCAUGGUUUACAUGCUACAGUCAAGAUGCGAAUCAUUAUUUGCUGCUCUAG | 32 |
miR-15b-2 | UUGAGGCCUUAAAGUACUGUAGCAGCACAUCAUGGUUUACAUGCUACAGUCAAGAUGCGAAUCAUUAUUUGCUGCUCUAGAAAUUUAAGGAAAUUCAU | 33 |
miR-16-1 | GUCAGCAGUGCCUUAGCAGCACGUAAAUAUUGGCGUUAAGAUUCUAAAAUUAUCUCCAGUAUUAACUGUGCUGCUGAAGUAAGGUUGAC | 34 |
miR-16-2 | GUUCCACUCUAGCAGCACGUAAAUAUUGGCGUAGUGAAAUAUAUAUUAAACACCAAUAUUACUGUGCUGCUUUAGUGUGAC | 35 |
miR-16-13 | GCAGUGCCUUAGCAGCACGUAAAUAUUGGCGUUAAGAUUCUAAAAUUAUCUCCAGUAUUAACUGUGCUGCUGAAGUAAGGU | 36 |
miR-17 | GUCAGAAUAAUGUCAAAGUGCUUACAGUGCAGGUAGUGAUAUGUGCAUCUACUGCAGUGAAGGCACUUGUAGCAUUAUGGUGAC | 37 |
miR-18 | UGUUCUAAGGUGCAUCUAGUGCAGAUAGUGAAGUAGAUUAGCAUCUACUGCCCUAAGUGCUCCUUCUGGCA | 38 |
miR-18-13 | UUUUUGUUCUAAGGUGCAUCUAGUGCAGAUAGUGAAGUAGAUUAGCAUCUACUGCCCUAAGUGCUCCUUCUGGCAUAAGAA | 39 |
miR-19a | GCAGUCCUCUGUUAGUUUUGCAUAGUUGCACUACAAGAAGAAUGUAGUUG UGCAAAUCUAUGCAAAACUGAUGGUGGCCUGC | 40 |
miR-19a-13 | CAGUCCUCUGUUAGUUUUGCAUAGUUGCACUACAAGAAGAAUGUAGUUGU GCAAAUCUAUGCAAAACUGAUGGUGGCCUG | 41 |
miR-19b-1 | CACUGUUCUAUGGUUAGUUUUGCAGGUUUGCAUCCAGCUGUGUGAUAUUCUGCUGUGCAAAUCCAUGCAAAACUGACUGUGGUAGUG | 42 |
miR-19b-2 | ACAUUGCUACUUACAAUUAGUUUUGCAGGUUUGCAUUUCAGCGUAUAUAUGUAUAUGUGGCUGUGCAAAUCCAUGCAAAACUGAUUGUGAUAAUGU | 43 |
miR-19b-13 | UUCUAUGGUUAGUUUUGCAGGUUUGCAUCCAGCUGUGUGAUAUUCUGCUG UGCAAAUCCAUGCAAAACUGACUGUGGUAG | 44 |
miR-19b-X | UUACAAUUAGUUUUGCAGGUUUGCAUUUCAGCGUAUAUAUGUAUAUGUGG CUGUGCAAAUCCAUGCAAAACUGAUUGUGAU | 45 |
miR-20(miR-20a) | GUAGCACUAAAGUGCUUAUAGUGCAGGUAGUGUUUAGUUAUCUACUGCAUUAUGAGCACUUAAAGUACUGC | 46 |
miR-21 | UGUCGGGUAGCUUAUCAGACUGAUGUUGACUGUUGAAUCUCAUGGCAACACCAGUCGAUGGGCUGUCUGACA | 47 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-21-17 | ACCUUGUCGGGUAGCUUAUCAGACUGAUGUUGACUGUUGAAUCUCAUGGCAACACCAGUCGAUGGGCUGUCUGACAUUUUG | 48 |
miR-22 | GGCUGAGCCGCAGUAGUUCUUCAGUGGCAAGCUUUAUGUCCUGACCCAGCUAAAGCUGCCAGUUGAAGAACUGUUGCCCUCUGCC | 49 |
miR-23a | GGCCGGCUGGGGUUCCUGGGGAUGGGAUUUGCUUCCUGUCACAAAUCACA UUGCCAGGGAUUUCCAACCGACC | 50 |
miR-23b | CUCAGGUGCUCUGGCUGCUUGGGUUCCUGGCAUGCUGAUUUGUGACUUAAGAUUAAAAUCACAUUGCCAGGGAUUACCACGCAACCACGACCUUGGC | 51 |
miR-23-19 | CCACGGCCGGCUGGGGUUCCUGGGGAUGGGAUUUGCUUCCUGUCACAAAU CACAUUGCCAGGGAUUUCCAACCGACCCUGA | 52 |
miR-24-1 | CUCCGGUGCCUACUGAGCUGAUAUCAGUUCUCAUUUUACACACUGGCUCA GUUCAGCAGGAACAGGAG | 53 |
miR-24-2 | CUCUGCCUCCCGUGCCUACUGAGCUGAAACACAGUUGGUUUGUGUACACU GGCUCAGUUCAGCAGGAACAGGG | 54 |
miR-24-19 | CCCUGGGCUCUGCCUCCCGUGCCUACUGAGCUGAAACACAGUUGGUUUGUGUACACUGGCUCAGUUCAGCAGGAACAGGGG | 55 |
miR-24-9 | CCCUCCGGUGCCUACUGAGCUGAUAUCAGUUCUCAUUUUACACACUGGCU CAGUUCAGCAGGAACAGCAUC | 56 |
miR-25 | GGCCAGUGUUGAGAGGCGGAGACUUGGGCAAUUGCUGGACGCUGCCCUGGGCAUUGCACUUGUCUCGGUCUGACAGUGCCGGCC | 57 |
miR-26a | AGGCCGUGGCCUCGUUCAAGUAAUCCAGGAUAGGCUGUGCAGGUCCCAAUGGCCUAUCUUGGUUACUUGCACGGGGACGCGGGCCU | 58 |
miR-26a-1 | GUGGCCUCGUUCAAGUAAUCCAGGAUAGGCUGUGCAGGUCCCAAUGGGCCUAUUCUUGGUUACUUGCACGGGGACGC | 59 |
miR-26a-2 | GGCUGUGGCUGGAUUCAAGUAAUCCAGGAUAGGCUGUUUCCAUCUGUGAGGCCUAUUCUUGAUUACUUGUUUCUGGAGGCAGCU | 60 |
miR-26b | CCGGGACCCAGUUCAAGUAAUUCAGGAUAGGUUGUGUGCUGUCCAGCCUGUUCUCCAUUACUUGGCUCGGGGACCGG | 61 |
miR-27a | CUGAGGAGCAGGGCUUAGCUGCUUGUGAGCAGGGUCCACACCAAGUCGUGUUCACAGUGGCUAAGUUCCGCCCCCCAG | 62 |
miR-27b-1 | AGGUGCAGAGCUUAGCUGAUUGGUGAACAGUGAUUGGUUUCCGCUUUGUU CACAGUGGCUAAGUUCUGCACCU | 63 |
miR-27b-2 | ACCUCUCUAACAAGGUGCAGAGCUUAGCUGAUUGGUGAACAGUGAUUGGUUUCCGCUUUGUUCACAGUGGCUAAGUUCUGCACCUGAAGAGAAGGUG | 64 |
miR-27-19 | CCUGAGGAGCAGGGCUUAGCUGCUUGUGAGCAGGGUCCACACCAAGUCGUGUUCACAGUGGCUAAGUUCCGCCCCCCAGG | 65 |
miR-28 | GGUCCUUGCCCUCAAGGAGCUCACAGUCUAUUGAGUUACCUUUCUGACUUUCCCACUAGAUUGUGAGCUCCUGGAGGGCAGGCACU | 66 |
miR-29a-2 | CCUUCUGUGACCCCUUAGAGGAUGACUGAUUUCUUUUGGUGUUCAGAGUCAAUAUAAUUUUCUAGCACCAUCUGAAAUCGGUUAUAAUGAUUGGGGAAGAGCACCAUG | 67 |
miR-29a | AUGACUGAUUUCUUUUGGUGUUCAGAGUCAAUAUAAUUUUCUAGCACCAU CUGAAAUCGGUUAU | 68 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-29b-1 | CUUCAGGAAGCUGGUUUCAUAUGGUGGUUUAGAUUUAAAUAGUGAUUGUCUAGCACCAUUUGAAAUCAGUGUUCUUGGGGG | 69 |
miR-29b-2 | CUUCUGGAAGCUGGUUUCACAUGGUGGCUUAGAUUUUUCCAUCUUUGUAUCUAGCACCAUUUGAAAUCAGUGUUUUAGGAG | 70 |
miR-29c | ACCACUGGCCCAUCUCUUACACAGGCUGACCGAUUUCUCCUGGUGUUCAGAGUCUGUUUUUGUCUAGCACCAUUUGAAAUCGGUUAUGAUGUAGGGGGAAAAGCAGCAGC | 71 |
miR-30a | GCGACUGUAAACAUCCUCGACUGGAAGCUGUGAAGCCACAGAUGGGCUUU CAGUCGGAUGUUUGCAGCUGC | 72 |
miR-30b-1 | AUGUAAACAUCCUACACUCAGCUGUAAUACAUGGAUUGGCUGGGAGGUGGAUGUUUACGU | 73 |
miR-30b-2 | ACCAAGUUUCAGUUCAUGUAAACAUCCUACACUCAGCUGUAAUACAUGGAUUGGCUGGGAGGUGGAUGUUUACUUCAGCUGACUUGGA | 74 |
miR-30c | AGAUACUGUAAACAUCCUACACUCUCAGCUGUGGAAAGUAAGAAAGCUGGGAGAAGGCUGUUUACUCUUUCU | 75 |
miR-30d | GUUGUUGUAAACAUCCCCGACUGGAAGCUGUAAGACACAGCUAAGCUUUCAGUCAGAUGUUUGCUGCUAC | 76 |
miR-30e | CUGUAAACAUCCUUGACUGGAAGCUGUAAGGUGUUCAGAGGAGCUUUCAGUCGGAUGUUUACAG | 77 |
miR-31 | GGAGAGGAGGCAAGAUGCUGGCAUAGCUGUUGAACUGGGAACCUGCUAUGCCAACAUAUUGCCAUCUUUCC | 78 |
miR-32 | GGAGAUAUUGCACAUUACUAAGUUGCAUGUUGUCACGGCCUCAAUGCAAUUUAGUGUGUGUGAUAUUUUC | 79 |
miR-33b | GGGGGCCGAGAGAGGCGGGCGGCCCCGCGGUGCAUUGCUGUUGCAUUGCACGUGUGUGAGGCGGGUGCAGUGCCUCGGCAGUGCAGCCCGGAGCCGGCCCCUGGCACCAC | 80 |
miR-33b-2 | ACCAAGUUUCAGUUCAUGUAAACAUCCUACACUCAGCUGUAAUACAUGGAUUGGCUGGGAGGUGGAUGUUUACUUCAGCUGACUUGGA | 81 |
miR-33 | CUGUGGUGCAUUGUAGUUGCAUUGCAUGUUCUGGUGGUACCCAUGCAAUGUUUCCACAGUGCAUCACAG | 82 |
miR-34-a | GGCCAGCUGUGAGUGUUUCUUUGGCAGUGUCUUAGCUGGUUGUUGUGAGCAAUAGUAAGGAAGCAAUCAGCAAGUAUACUGCCCUAGAAGUGCUGCACGUUGUGGGGCCC | 83 |
miR-34-b | GUGCUCGGUUUGUAGGCAGUGUCAUUAGCUGAUUGUACUGUGGUGGUUACAAUCACUAACUCCACUGCCAUCAAAACAAGGCAC | 84 |
miR-34-c | AGUCUAGUUACUAGGCAGUGUAGUUAGCUGAUUGCUAAUAGUACCAAUCACUAACCACACGGCCAGGUAAAAAGAUU | 85 |
miR-91-13 | UCAGAAUAAUGUCAAAGUGCUUACAGUGCAGGUAGUGAUAUGUGCAUCUACUGCAGUGAAGGCACUUGUAGCAUUAUGGUGA | 86 |
miR-92-1 | CUUUCUACACAGGUUGGGAUCGGUUGCAAUGCUGUGUUUCUGUAUGGUAU UGCACUUGUCCCGGCCUGUUGAGUUUGG | 87 |
miR-92-2 | UCAUCCCUGGGUGGGGAUUUGUUGCAUUACUUGUGUUCUAUAUAAAGUAU UGCACUUGUCCCGGCCUGUGGAAGA | 88 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-93-1(miR-93-2) | CUGGGGGCUCCAAAGUGCUGUUCGUGCAGGUAGUGUGAUUACCCAACCUACUGCUGAGCUAGCACUUCCCGAGCCCCCGG | 89 |
miR-95-4 | AACACAGUGGGCACUCAAUAAAUGUCUGUUGAAUUGAAAUGCGUUACAUU CAACGGGUAUUUAUUGAGCACCCACUCUGUG | 90 |
miR-96-7 | UGGCCGAUUUUGGCACUAGCACAUUUUUGCUUGUGUCUCUCCGCUCUGAGCAAUCAUGUGCAGUGCCAAUAUGGGAAA | 91 |
miR-97-6(miR-30*) | GUGAGCGACUGUAAACAUCCUCGACUGGAAGCUGUGAAGCCACAGAUGGGCUUUCAGUCGGAUGUUUGCAGCUGCCUACU | 92 |
miR-98 | GUGAGGUAGUAAGUUGUAUUGUUGUGGGGUAGGGAUAUUAGGCCCCAAUUAGAAGAUAACUAUACAACUUACUACUUUCC | 93 |
miR-99b | GGCACCCACCCGUAGAACCGACCUUGCGGGGCCUUCGCCGCACACAAGCUCGUGUCUGUGGGUCCGUGUC | 94 |
miR-99a | CCCAUUGGCAUAAACCCGUAGAUCCGAUCUUGUGGUGAAGUGGACCGCACAAGCUCGCUUCUAUGGGUCUGUGUCAGUGUG | 95 |
miR-100-1/2 | AAGAGAGAAGAUAUUGAGGCCUGUUGCCACAAACCCGUAGAUCCGAACUU GUGGUAUUAGUCCGCACAAGCUUGUAUCUAUAGGUAUGUGUCUGUUAGGCAAUCUCAC | 96 |
miR-100-11 | CCUGUUGCCACAAACCCGUAGAUCCGAACUUGUGGUAUUAGUCCGCACAAGCUUGUAUCUAUAGGUAUGUGUCUGUUAGG | 97 |
miR-101-1/2 | AGGCUGCCCUGGCUCAGUUAUCACAGUGCUGAUGCUGUCUAUUCUAAAGGUACAGUACUGUGAUAACUGAAGGAUGGCAGCCAUCUUACCUUCCAUCAGAGGAGCCUCAC | 98 |
miR-101 | UCAGUUAUCACAGUGCUGAUGCUGUCCAUUCUAAAGGUACAGUACUGUGA UAACUGA | 99 |
miR-101-1 | UGCCCUGGCUCAGUUAUCACAGUGCUGAUGCUGUCUAUUCUAAAGGUACA GUACUGUGAUAACUGAAGGAUGGCA | 100 |
miR-101-2 | ACUGUCCUUUUUCGGUUAUCAUGGUACCGAUGCUGUAUAUCUGAAAGGUA CAGUACUGUGAUAACUGAAGAAUGGUGGU | 101 |
miR-101-9 | UGUCCUUUUUCGGUUAUCAUGGUACCGAUGCUGUAUAUCUGAAAGGUACA GUACUGUGAUAACUGAAGAAUGGUG | 102 |
miR-102-1 | CUUCUGGAAGCUGGUUUCACAUGGUGGCUUAGAUUUUUCCAUCUUUGUAUCUAGCACCAUUUGAAAUCAGUGUUUUAGGAG | 103 |
miR-102-7.1(miR-102-7.2) | CUUCAGGAAGCUGGUUUCAUAUGGUGGUUUAGAUUUAAAUAGUGAUUGUCUAGCACCAUUUGAAAUCAGUGUUCUUGGGGG | 104 |
miR-103-2 | UUGUGCUUUCAGCUUCUUUACAGUGCUGCCUUGUAGCAUUCAGGUCAAGC AACAUUGUACAGGGCUAUGAAAGAACCA | 105 |
miR-103-1 | UACUGCCCUCGGCUUCUUUACAGUGCUGCCUUGUUGCAUAUGGAUCAAGC AGCAUUGUACAGGGCUAUGAAGGCAUUG | 106 |
miR-104-17 | AAAUGUCAGACAGCCCAUCGACUGGUGUUGCCAUGAGAUUCAACAGUCAA CAUCAGUCUGAUAAGCUACCCGACAAGG | 107 |
miR-105-1 | UGUGCAUCGUGGUCAAAUGCUCAGACUCCUGUGGUGGCUGCUCAUGCACCACGGAUGUUUGAGCAUGUGCUACGGUGUCUA | 108 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-105-2 | UGUGCAUCGUGGUCAAAUGCUCAGACUCCUGUGGUGGCUGCUUAUGCACCACGGAUGUUUGAGCAUGUGCUAUGGUGUCUA | 109 |
miR-106-a | CCUUGGCCAUGUAAAAGUGCUUACAGUGCAGGUAGCUUUUUGAGAUCUACUGCAAUGUAAGCACUUCUUACAUUACCAUGG | 110 |
miR-106-b | CCUGCCGGGGCUAAAGUGCUGACAGUGCAGAUAGUGGUCCUCUCCGUGCUACCGCACUGUGGGUACUUGCUGCUCCAGCAGG | 111 |
miR-107 | CUCUCUGCUUUCAGCUUCUUUACAGUGUUGCCUUGUGGCAUGGAGUUCAAGCAGCAUUGUACAGGGCUAUCAAAGCACAGA | 112 |
miR-108-1-小 | ACACUGCAAGAACAAUAAGGAUUUUUAGGGGCAUUAUGACUGAGUCAGAAAACACAGCUGCCCCUGAAAGUCCCUCAUUUUUCUUGCUGU | 113 |
miR-108-2-小 | ACUGCAAGAGCAAUAAGGAUUUUUAGGGGCAUUAUGAUAGUGGAAUGGAAACACAUCUGCCCCCAAAAGUCCCUCAUUUU | 114 |
miR-122a-1 | CCUUAGCAGAGCUGUGGAGUGUGACAAUGGUGUUUGUGUCUAAACUAUCAAACGCCAUUAUCACACUAAAUAGCUACUGCUAGGC | 115 |
miR-122a-2 | AGCUGUGGAGUGUGACAAUGGUGUUUGUGUCCAAACUAUCAAACGCCAUUAUCACACUAAAUAGCU | 116 |
miR-123 | ACAUUAUUACUUUUGGUACGCGCUGUGACACUUCAAACUCGUACCGUGAGUAAUAAUGCGC | 117 |
miR-124a-1 | AGGCCUCUCUCUCCGUGUUCACAGCGGACCUUGAUUUAAAUGUCCAUACAAUUAAGGCACGCGGUGAAUGCCAAGAAUGGGGCUG | 118 |
miR-124a-2 | AUCAAGAUUAGAGGCUCUGCUCUCCGUGUUCACAGCGGACCUUGAUUUAAUGUCAUACAAUUAAGGCACGCGGUGAAUGCCAAGAGCGGAGCCUACGGCUGCACUUGAAG | 119 |
miR-124a-3 | UGAGGGCCCCUCUGCGUGUUCACAGCGGACCUUGAUUUAAUGUCUAUACAAUUAAGGCACGCGGUGAAUGCCAAGAGAGGCGCCUCC | 120 |
miR-124a | CUCUGCGUGUUCACAGCGGACCUUGAUUUAAUGUCUAUACAAUUAAGGCA CGCGGUGAAUGCCAAGAG | 121 |
miR-124b | CUCUCCGUGUUCACAGCGGACCUUGAUUUAAUGUCAUACAAUUAAGGCAC GCGGUGAAUGCCAAGAG | 122 |
miR-125a-1 | UGCCAGUCUCUAGGUCCCUGAGACCCUUUAACCUGUGAGGACAUCCAGGGUCACAGGUGAGGUUCUUGGGAGCCUGGCGUCUGGCC | 123 |
miR-125a-2 | GGUCCCUGAGACCCUUUAACCUGUGAGGACAUCCAGGGUCACAGGUGAGGUUCUUGGGAGCCUGG | 124 |
miR-125b-1 | UGCGCUCCUCUCAGUCCCUGAGACCCUAACUUGUGAUGUUUACCGUUUAAAUCCACGGGUUAGGCUCUUGGGAGCUGCGAGUCGUGCU | 125 |
miR-125b-2 | ACCAGACUUUUCCUAGUCCCUGAGACCCUAACUUGUGAGGUAUUUUAGUAACAUCACAAGUCAGGCUCUUGGGACCUAGGCGGAGGGGA | 126 |
miR-126-1 | CGCUGGCGACGGGACAUUAUUACUUUUGGUACGCGCUGUGACACUUCAAACUCGUACCGUGAGUAAUAAUGCGCCGUCCACGGCA | 127 |
miR-126-2 | ACAUUAUUACUUUUGGUACGCGCUGUGACACUUCAAACUCGUACCGUGAG UAAUAAUGCGC | 128 |
miR-127-1 | UGUGAUCACUGUCUCCAGCCUGCUGAAGCUCAGAGGGCUCUGAUUCAGAAAGAUCAUCGGAUCCGUCUGAGCUUGGCUGGUCGGAAGUCUCAUCAUC | 129 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-127-2 | CCAGCCUGCUGAAGCUCAGAGGGCUCUGAUUCAGAAAGAUCAUCGGAUCC GUCUGAGCUUGGCUGGUCGG | 130 |
miR-128a | UGAGCUGUUGGAUUCGGGGCCGUAGCACUGUCUGAGAGGUUUACAUUUCU CACAGUGAACCGGUCUCUUUUUCAGCUGCUUC | 131 |
miR-128b | GCCCGGCAGCCACUGUGCAGUGGGAAGGGGGGCCGAUACACUGUACGAGAGUGAGUAGCAGGUCUCACAGUGAACCGGUCUCUUUCCCUACUGUGUCACACUCCUAAUGG | 132 |
miR-128 | GUUGGAUUCGGGGCCGUAGCACUGUCUGAGAGGUUUACAUUUCUCACAGU GAACCGGUCUCUUUUUCAGC | 133 |
miR-129-1 | UGGAUCUUUUUGCGGUCUGGGCUUGCUGUUCCUCUCAACAGUAGUCAGGAAGCCCUUACCCCAAAAAGUAUCUA | 134 |
miR-129-2 | UGCCCUUCGCGAAUCUUUUUGCGGUCUGGGCUUGCUGUACAUAACUCAAUAGCCGGAAGCCCUUACCCCAAAAAGCAUUUGCGGAGGGCG | 135 |
miR-130a | UGCUGCUGGCCAGAGCUCUUUUCACAUUGUGCUACUGUCUGCACCUGUCACUAGCAGUGCAAUGUUAAAAGGGCAUUGGCCGUGUAGUG | 136 |
miR-131-1 | GCCAGGAGGCGGGGUUGGUUGUUAUCUUUGGUUAUCUAGCUGUAUGAGUGGUGUGGAGUCUUCAUAAAGCUAGAUAACCGAAAGUAAAAAUAACCCCAUACACUGCGCAG | 137 |
miR-131-3 | CACGGCGCGGCAGCGGCACUGGCUAAGGGAGGCCCGUUUCUCUCUUUGGUUAUCUAGCUGUAUGAGUGCCACAGAGCCGUCAUAAAGCUAGAUAACCGAA AGUAGAAAUG | 138 |
miR-131 | GUUGUUAUCUUUGGUUAUCUAGCUGUAUGAGUGUAUUGGUCUUCAUAAAG CUAGAUAACCGAAAGUAAAAAC | 139 |
miR-132-1 | CCGCCCCCGCGUCUCCAGGGCAACCGUGGCUUUCGAUUGUUACUGUGGGAACUGGAGGUAACAGUCUACAGCCAUGGUCGCCCCGCAGCACGCCCACGCGC | 140 |
miR-132-2 | GGGCAACCGUGGCUUUCGAUUGUUACUGUGGGAACUGGAGGUAACAGUCU ACAGCCAUGGUCGCCC | 141 |
miR-133a-1 | ACAAUGCUUUGCUAGAGCUGGUAAAAUGGAACCAAAUCGCCUCUUCAAUGGAUUUGGUCCCCUUCAACCAGCUGUAGCUAUGCAUUGA | 142 |
miR-133a-2 | GGGAGCCAAAUGCUUUGCUAGAGCUGGUAAAAUGGAACCAAAUCGACUGUCCAAUGGAUUUGGUCCCCUUCAACCAGCUGUAGCUGUGCAUUGAUGGCGCCG | 143 |
miR-133 | GCUAGAGCUGGUAAAAUGGAACCAAAUCGCCUCUUCAAUGGAUUUGGUCC CCUUCAACCAGCUGUAGC | 144 |
miR-133b | CCUCAGAAGAAAGAUGCCCCCUGCUCUGGCUGGUCAAACGGAACCAAGUCCGUCUUCCUGAGAGGUUUGGUCCCCUUCAACCAGCUACAGCAGGGCUGGCAAUGCCCAGUCCUUGGAGA | 145 |
miR-133b-小 | GCCCCCUGCUCUGGCUGGUCAAACGGAACCAAGUCCGUCUUCCUGAGAGGUUUGGUCCCCUUCAACCAGCUACAGCAGGG | 146 |
miR-134-1 | CAGGGUGUGUGACUGGUUGACCAGAGGGGCAUGCACUGUGUUCACCCUGUGGGCCACCUAGUCACCAACCCUC | 147 |
miR-134-2 | AGGGUGUGUGACUGGUUGACCAGAGGGGCAUGCACUGUGUUCACCCUGUGGGCCACCUAGUCACCAACCCU | 148 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-135a-1 | AGGCCUCGCUGUUCUCUAUGGCUUUUUAUUCCUAUGUGAUUCUACUGCUCACUCAUAUAGGGAUUGGAGCCGUGGCGCACGGCGGGGACA | 149 |
miR-135a-2(miR-135-2) | AGAUAAAUUCACUCUAGUGCUUUAUGGCUUUUUAUUCCUAUGUGAUAGUAAUAAAGUCUCAUGUAGGGAUGGAAGCCAUGAAAUACAUUGUGAAAAAUCA | 150 |
miR-135 | CUAUGGCUUUUUAUUCCUAUGUGAUUCUACUGCUCACUCAUAUAGGGAUUGGAGCCGUGG | 151 |
miR-135b | CACUCUGCUGUGGCCUAUGGCUUUUCAUUCCUAUGUGAUUGCUGUCCCAAACUCAUGUAGGGCUAAAAGCCAUGGGCUACAGUGAGGGGCGAGCUCC | 152 |
miR-136-1 | UGAGCCCUCGGAGGACUCCAUUUGUUUUGAUGAUGGAUUCUUAUGCUCCAUCAUCGUCUCAAAUGAGUCUUCAGAGGGUUCU | 153 |
miR-136-2 | GAGGACUCCAUUUGUUUUGAUGAUGGAUUCUUAUGCUCCAUCAUCGUCUCAAAUGAGUCUUC | 154 |
miR-137 | CUUCGGUGACGGGUAUUCUUGGGUGGAUAAUACGGAUUACGUUGUUAUUG CUUAAGAAUACGCGUAGUCGAGG | 155 |
miR-138-1 | CCCUGGCAUGGUGUGGUGGGGCAGCUGGUGUUGUGAAUCAGGCCGUUGCCAAUCAGAGAACGGCUACUUCACAACACCAGGGCCACACCACACUACAGG | 156 |
miR-138-2 | CGUUGCUGCAGCUGGUGUUGUGAAUCAGGCCGACGAGCAGCGCAUCCUCUUACCCGGCUAUUUCACGACACCAGGGUUGCAUCA | 157 |
miR-138 | CAGCUGGUGUUGUGAAUCAGGCCGACGAGCAGCGCAUCCUCUUACCCGGCUAUUUCACGACACCAGGGUUG | 158 |
miR-139 | GUGUAUUCUACAGUGCACGUGUCUCCAGUGUGGCUCGGAGGCUGGAGACGCGGCCCUGUUGGAGUAAC | 159 |
miR-140 | UGUGUCUCUCUCUGUGUCCUGCCAGUGGUUUUACCCUAUGGUAGGUUACGUCAUGCUGUUCUACCACAGGGUAGAACCACGGACAGGAUACCGGGGCACC | 160 |
miR-140as | UCCUGCCAGUGGUUUUACCCUAUGGUAGGUUACGUCAUGCUGUUCUACCA CAGGGUAGAACCACGGACAGGA | 161 |
miR-140s | CCUGCCAGUGGUUUUACCCUAUGGUAGGUUACGUCAUGCUGUUCUACCAC AGGGUAGAACCACGGACAGG | 162 |
miR-141-1 | CGGCCGGCCCUGGGUCCAUCUUCCAGUACAGUGUUGGAUGGUCUAAUUGUGAAGCUCCUAACACUGUCUGGUAAAGAUGGCUCCCGGGUGGGUUC | 163 |
miR-141-2 | GGGUCCAUCUUCCAGUACAGUGUUGGAUGGUCUAAUUGUGAAGCUCCUAA CACUGUCUGGUAAAGAUGGCCC | 164 |
miR-142 | ACCCAUAAAGUAGAAAGCACUACUAACAGCACUGGAGGGUGUAGUGUUUC CUACUUUAUGGAUG | 165 |
miR-143-1 | GCGCAGCGCCCUGUCUCCCAGCCUGAGGUGCAGUGCUGCAUCUCUGGUCAGUUGGGAGUCUGAGAUGAAGCACUGUAGCUCAGGAAGAGAGAAGUUGUUCUGCAGC | 166 |
miR-143-2 | CCUGAGGUGCAGUGCUGCAUCUCUGGUCAGUUGGGAGUCUGAGAUGAAGC ACUGUAGCUCAGG | 167 |
miR-144-1 | UGGGGCCCUGGCUGGGAUAUCAUCAUAUACUGUAAGUUUGCGAUGAGACACUACAGUAUAGAUGAUGUACUAGUCCGGGCACCCCC | 168 |
miR-144-2 | GGCUGGGAUAUCAUCAUAUACUGUAAGUUUGCGAUGAGACACUACAGUAU AGAUGAUGUACUAGUC | 169 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-145-1 | CACCUUGUCCUCACGGUCCAGUUUUCCCAGGAAUCCCUUAGAUGCUAAGAUGGGGAUUCCUGGAAAUACUGUUCUUGAGGUCAUGGUU | 170 |
miR-145-2 | CUCACGGUCCAGUUUUCCCAGGAAUCCCUUAGAUGCUAAGAUGGGGAUUCCUGGAAAUACUGUUCUUGAG | 171 |
miR-146-1 | CCGAUGUGUAUCCUCAGCUUUGAGAACUGAAUUCCAUGGGUUGUGUCAGUGUCAGACCUCUGAAAUUCAGUUCUUCAGCUGGGAUAUCUCUGUCAUCGU | 172 |
miR-146-2 | AGCUUUGAGAACUGAAUUCCAUGGGUUGUGUCAGUGUCAGACCUGUGAAAUUCAGUUCUUCAGCU | 173 |
miR-147 | AAUCUAAAGACAACAUUUCUGCACACACACCAGACUAUGGAAGCCAGUGU GUGGAAAUGCUUCUGCUAGAUU | 174 |
miR-148a(miR-148) | GAGGCAAAGUUCUGAGACACUCCGACUCUGAGUAUGAUAGAAGUCAGUGC ACUACAGAACUUUGUCUC | 175 |
miR-148b | CAAGCACGAUUAGCAUUUGAGGUGAAGUUCUGUUAUACACUCAGGCUGUGGCUCUCUGAAAGUCAGUGCAUCACAGAACUUUGUCUCGAAAGCUUUCUA | 176 |
miR-148b-小 | AAGCACGAUUAGCAUUUGAGGUGAAGUUCUGUUAUACACUCAGGCUGUGGCUCUCUGAAAGUCAGUGCAU | 177 |
miR-149-1 | GCCGGCGCCCGAGCUCUGGCUCCGUGUCUUCACUCCCGUGCUUGUCCGAGGAGGGAGGGAGGGACGGGGGCUGUGCUGGGGCAGCUGGA | 178 |
miR-149-2 | GCUCUGGCUCCGUGUCUUCACUCCCGUGCUUGUCCGAGGAGGGAGGGAGGGAC | 179 |
miR-150-1 | CUCCCCAUGGCCCUGUCUCCCAACCCUUGUACCAGUGCUGGGCUCAGACCCUGGUACAGGCCUGGGGGACAGGGACCUGGGGAC | 180 |
miR-150-2 | CCCUGUCUCCCAACCCUUGUACCAGUGCUGGGCUCAGACCCUGGUACAGGCCUGGGGGACAGGG | 181 |
miR-151 | UUUCCUGCCCUCGAGGAGCUCACAGUCUAGUAUGUCUCAUCCCCUACUAG ACUGAAGCUCCUUGAGGACAGG | 182 |
miR-151-2 | CCUGUCCUCAAGGAGCUUCAGUCUAGUAGGGGAUGAGACAUACUAGACUGUGAGCUCCUCGAGGGCAGG | 183 |
miR-152-1 | UGUCCCCCCCGGCCCAGGUUCUGUGAUACACUCCGACUCGGGCUCUGGAGCAGUCAGUGCAUGACAGAACUUGGGCCCGGAAGGACC | 184 |
miR-152-2 | GGCCCAGGUUCUGUGAUACACUCCGACUCGGGCUCUGGAGCAGUCAGUGC AUGACAGAACUUGGGCCCCGG | 185 |
miR-153-1-1 | CUCACAGCUGCCAGUGUCAUUUUUGUGAUCUGCAGCUAGUAUUCUCACUCCAGUUGCAUAGUCACAAAAGUGAUCAUUGGCAGGUGUGGC | 186 |
miR-153-1-2 | UCUCUCUCUCCCUCACAGCUGCCAGUGUCAUUGUCACAAAAGUGAUCAUUGGCAGGUGUGGCUGCUGCAUG | 187 |
miR-153-2-1 | AGCGGUGGCCAGUGUCAUUUUUGUGAUGUUGCAGCUAGUAAUAUGAGCCCAGUUGCAUAGUCACAAAAGUGAUCAUUGGAAACUGUG | 188 |
miR-153-2-2 | CAGUGUCAUUUUUGUGAUGUUGCAGCUAGUAAUAUGAGCCCAGUUGCAUA GUCACAAAAGUGAUCAUUG | 189 |
miR-154-1 | GUGGUACUUGAAGAUAGGUUAUCCGUGUUGCCUUCGCUUUAUUUGUGACGAAUCAUACACGGUUGACCUAUUUUUCAGUACCAA | 190 |
miR-154-2 | GAAGAUAGGUUAUCCGUGUUGCCUUCGCUUUAUUUGUGACGAAUCAUACA CGGUUGACCUAUUUUU | 191 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-155 | CUGUUAAUGCUAAUCGUGAUAGGGGUUUUUGCCUCCAACUGACUCCUACAUAUUAGCAUUAACAG | 192 |
miR-156=miR-157=重叠miR-141 | CCUAACACUGUCUGGUAAAGAUGGCUCCCGGGUGGGUUCUCUCGGCAGUAACCUUCAGGGAGCCCUGAAGACCAUGGAGGAC | 193 |
miR-158-小=miR-192 | GCCGAGACCGAGUGCACAGGGCUCUGACCUAUGAAUUGACAGCCAGUGCUCUCGUCUCCCCUCUGGCUGCCAAUUCCAUAGGUCACAGGUAUGUUCGCCUCAAUGCCAGC | 194 |
miR-159-1-小 | UCCCGCCCCCUGUAACAGCAACUCCAUGUGGAAGUGCCCACUGGUUCCAGUGGGGCUGCUGUUAUCUGGGGCGAGGGCCA | 195 |
miR-161-小 | AAAGCUGGGUUGAGAGGGCGAAAAAGGAUGAGGUGACUGGUCUGGGCUACGCUAUGCUGCGGCGCUCGGG | 196 |
miR-163-1b-小 | CAUUGGCCUCCUAAGCCAGGGAUUGUGGGUUCGAGUCCCACCCGGGGUAAAGAAAGGCCGAAUU | 197 |
miR-163-3-小 | CCUAAGCCAGGGAUUGUGGGUUCGAGUCCCACCUGGGGUAGAGGUGAAAGUUCCUUUUACGGAAUUUUUU | 198 |
miR-162 | CAAUGUCAGCAGUGCCUUAGCAGCACGUAAAUAUUGGCGUUAAGAUUCUAAAAUUAUCUCCAGUAUUAACUGUGCUGCUGAAGUAAGGUUGACCAUACUCUACAGUUG | 199 |
miR-175-小=miR-224 | GGGCUUUCAAGUCACUAGUGGUUCCGUUUAGUAGAUGAUUGUGCAUUGUUUCAAAAUGGUGCCCUAGUGACUACAAAGCCC | 200 |
miR-177-小 | ACGCAAGUGUCCUAAGGUGAGCUCAGGGAGCACAGAAACCUCCAGUGGAACAGAAGGGCAAAAGCUCAUU | 201 |
miR-180-小 | CAUGUGUCACUUUCAGGUGGAGUUUCAAGAGUCCCUUCCUGGUUCACCGUCUCCUUUGCUCUUCCACAAC | 202 |
miR-181a | AGAAGGGCUAUCAGGCCAGCCUUCAGAGGACUCCAAGGAACAUUCAACGC UGUCGGUGAGUUUGGGAUUUGAAAAAACCACUGACCGUUGACUGUACCUUGGGGUCCUUA | 203 |
miR-181b-1 | CCUGUGCAGAGAUUAUUUUUUAAAAGGUCACAAUCAACAUUCAUUGCUGU CGGUGGGUUGAACUGUGUGGACAAGCUCACUGAACAAUGAAUGCAACUGUGGCCCCGCUU | 204 |
miR-181b-2 | CUGAUGGCUGCACUCAACAUUCAUUGCUGUCGGUGGGUUUGAGUCUGAAUCAACUCACUGAUCAAUGAAUGCAAACUGCGGACCAAACA | 205 |
miR-181c | CGGAAAAUUUGCCAAGGGUUUGGGGGAACAUUCAACCUGUCGGUGAGUUUGGGCAGCUCAGGCAAACCAUCGACCGUUGAGUGGACCCUGAGGCCUGGAAUUGCCAUCCU | 206 |
miR-182-as | GAGCUGCUUGCCUCCCCCCGUUUUUGGCAAUGGUAGAACUCACACUGGUGAGGUAACAGGAUCCGGUGGUUCUAGACUUGCCAACUAUGGGGCGAGGACUCAGCCGGCAC | 207 |
miR-182 | UUUUUGGCAAUGGUAGAACUCACACUGGUGAGGUAACAGGAUCCGGUGGU UCUAGACUUGCCAACUAUGG | 208 |
miR-183 | CCGCAGAGUGUGACUCCUGUUCUGUGUAUGGCACUGGUAGAAUUCACUGUGAACAGUCUCAGUCAGUGAAUUACCGAAGGGCCAUAAACAGAGCAGAGACAGAUCCACGA | 209 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-184-1 | CCAGUCACGUCCCCUUAUCACUUUUCCAGCCCAGCUUUGUGACUGUAAGUGUUGGACGGAGAACUGAUAAGGGUAGGUGAUUGA | 210 |
miR-184-2 | CCUUAUCACUUUUCCAGCCCAGCUUUGUGACUGUAAGUGUUGGACGGAGA ACUGAUAAGGGUAGG | 211 |
miR-185-1 | AGGGGGCGAGGGAUUGGAGAGAAAGGCAGUUCCUGAUGGUCCCCUCCCCAGGGGCUGGCUUUCCUCUGGUCCUUCCCUCCCA | 212 |
miR-185-2 | AGGGAUUGGAGAGAAAGGCAGUUCCUGAUGGUCCCCUCCCCAGGGGCUGGCUUUCCUCUGGUCCUU | 213 |
miR-186-1 | UGCUUGUAACUUUCCAAAGAAUUCUCCUUUUGGGCUUUCUGGUUUUAUUUUAAGCCCAAAGGUGAAUUUUUUGGGAAGUUUGAGCU | 214 |
miR-186-2 | ACUUUCCAAAGAAUUCUCCUUUUGGGCUUUCUGGUUUUAUUUUAAGCCCAAAGGUGAAUUUUUUGGGAAGU | 215 |
miR-187 | GGUCGGGCUCACCAUGACACAGUGUGAGACUCGGGCUACAACACAGGACCCGGGGCGCUGCUCUGACCCCUCGUGUCUUGUGUUGCAGCCGGAGGGACGCAGGUCCGCA | 216 |
miR-188-1 | UGCUCCCUCUCUCACAUCCCUUGCAUGGUGGAGGGUGAGCUUUCUGAAAACCCCUCCCACAUGCAGGGUUUGCAGGAUGGCGAGCC | 217 |
miR-188-2 | UCUCACAUCCCUUGCAUGGUGGAGGGUGAGCUUUCUGAAAACCCCUCCCACAUGCAGGGUUUGCAGGA | 218 |
miR-189-1 | CUGUCGAUUGGACCCGCCCUCCGGUGCCUACUGAGCUGAUAUCAGUUCUCAUUUUACACACUGGCUCAGUUCAGCAGGAACAGGAGUCGAGCCCUUGAGCAA | 219 |
miR-189-2 | CUCCGGUGCCUACUGAGCUGAUAUCAGUUCUCAUUUUACACACUGGCUCAGUUCAGCAGGAACAGGAG | 220 |
miR-190-1 | UGCAGGCCUCUGUGUGAUAUGUUUGAUAUAUUAGGUUGUUAUUUAAUCCAACUAUAUAUCAAACAUAUUCCUACAGUGUCUUGCC | 221 |
miR-190-2 | CUGUGUGAUAUGUUUGAUAUAUUAGGUUGUUAUUUAAUCCAACUAUAUAUCAAACAUAUUCCUACAG | 222 |
miR-191-1 | CGGCUGGACAGCGGGCAACGGAAUCCCAAAAGCAGCUGUUGUCUCCAGAGCAUUCCAGCUGCGCUUGGAUUUCGUCCCCUGCUCUCCUGCCU | 223 |
miR-191-2 | AGCGGGCAACGGAAUCCCAAAAGCAGCUGUUGUCUCCAGAGCAUUCCAGCUGCGCUUGGAUUUCGUCCCCUGCU | 224 |
miR-192-2/3 | CCGAGACCGAGUGCACAGGGCUCUGACCUAUGAAUUGACAGCCAGUGCUCUCGUCUCCCCUCUGGCUGCCAAUUCCAUAGGUCACAGGUAUGUUCGCCUCAAUGCCAG | 225 |
miR-192 | GCCGAGACCGAGUGCACAGGGCUCUGACCUAUGAAUUGACAGCCAGUGCUCUCGUCUCCCCUCUGGCUGCCAAUUCCAUAGGUCACAGGUAUGUUCGCCUCAAUGCCAGC | 226 |
miR-193-1 | CGAGGAUGGGAGCUGAGGGCUGGGUCUUUGCGGGCGAGAUGAGGGUGUCGGAUCAACUGGCCUACAAAGUCCCAGUUCUCGGCCCCCG | 227 |
miR-193-2 | GCUGGGUCUUUGCGGGCGAGAUGAGGGUGUCGGAUCAACUGGCCUACAAA GUCCCAGU | 228 |
miR-194-1 | AUGGUGUUAUCAAGUGUAACAGCAACUCCAUGUGGACUGUGUACCAAUUUCCAGUGGAGAUGCUGUUACUUUUGAUGGUUACCAA | 229 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-194-2 | GUGUAACAGCAACUCCAUGUGGACUGUGUACCAAUUUCCAGUGGAGAUGCUGUUACUUUUGAU | 230 |
miR-195-1 | AGCUUCCCUGGCUCUAGCAGCACAGAAAUAUUGGCACAGGGAAGCGAGUCUGCCAAUAUUGGCUGUGCUGCUCCAGGCAGGGUGGUG | 231 |
miR-195-2 | UAGCAGCACAGAAAUAUUGGCACAGGGAAGCGAGUCUGCCAAUAUUGGCU GUGCUGCU | 232 |
miR-196-1 | CUAGAGCUUGAAUUGGAACUGCUGAGUGAAUUAGGUAGUUUCAUGUUGUU GGGCCUGGGUUUCUGAACACAACAACAUUAAACCACCCGAUUCACGGCAGUUACUGCUCC | 233 |
miR-196a-1 | GUGAAUUAGGUAGUUUCAUGUUGUUGGGCCUGGGUUUCUGAACACAACAACAUUAAACCACCCGAUUCAC | 234 |
miR-196a-2(miR-196-2) | UGCUCGCUCAGCUGAUCUGUGGCUUAGGUAGUUUCAUGUUGUUGGGAUUGAGUUUUGAACUCGGCAACAAGAAACUGCCUGAGUUACAUCAGUCGGUUUUCGUCGAGGGC | 235 |
miR-196 | GUGAAUUAGGUAGUUUCAUGUUGUUGGGCCUGGGUUUCUGAACACAACAACAUUAAACCACCCGAUUCAC | 236 |
miR-196b | ACUGGUCGGUGAUUUAGGUAGUUUCCUGUUGUUGGGAUCCACCUUUCUCUCGACAGCACGACACUGCCUUCAUUACUUCAGUUG | 237 |
miR-197 | GGCUGUGCCGGGUAGAGAGGGCAGUGGGAGGUAAGAGCUCUUCACCCUUC ACCACCUUCUCCACCCAGCAUGGCC | 238 |
miR-197-2 | GUGCAUGUGUAUGUAUGUGUGCAUGUGCAUGUGUAUGUGUAUGAGUGCAUGCGUGUGUGC | 239 |
miR-198 | UCAUUGGUCCAGAGGGGAGAUAGGUUCCUGUGAUUUUUCCUUCUUCUCUAUAGAAUAAAUGA | 240 |
miR-199a-1 | GCCAACCCAGUGUUCAGACUACCUGUUCAGGAGGCUCUCAAUGUGUACAG UAGUCUGCACAUUGGUUAGGC | 241 |
miR-199a-2 | AGGAAGCUUCUGGAGAUCCUGCUCCGUCGCCCCAGUGUUCAGACUACCUG UUCAGGACAAUGCCGUUGUACAGUAGUCUGCACAUUGGUUAGACUGGGCAAGGGAGAGCA | 242 |
miR-199b | CCAGAGGACACCUCCACUCCGUCUACCCAGUGUUUAGACUAUCUGUUCAGGACUCCCAAAUUGUACAGUAGUCUGCACAUUGGUUAGGCUGGGCUGGGUUAGACCCUCGG | 243 |
miR-199s | GCCAACCCAGUGUUCAGACUACCUGUUCAGGAGGCUCUCAAUGUGUACAG UAGUCUGCACAUUGGUUAGGC | 244 |
miR-200a | GCCGUGGCCAUCUUACUGGGCAGCAUUGGAUGGAGUCAGGUCUCUAAUAC UGCCUGGUAAUGAUGACGGC | 245 |
miR-200b | CCAGCUCGGGCAGCCGUGGCCAUCUUACUGGGCAGCAUUGGAUGGAGUCAGGUCUCUAAUACUGCCUGGUAAUGAUGACGGCGGAGCCCUGCACG | 246 |
miR-200c | CCCUCGUCUUACCCAGCAGUGUUUGGGUGCGGUUGGGAGUCUCUAAUACU GCCGGGUAAUGAUGGAGG | 247 |
miR-202 | GUUCCUUUUUCCUAUGCAUAUACUUCUUUGAGGAUCUGGCCUAAAGAGGU AUAGGGCAUGGGAAGAUGGAGC | 248 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-203 | GUGUUGGGGACUCGCGCGCUGGGUCCAGUGGUUCUUAACAGUUCAACAGUUCUGUAGCGCAAUUGUGAAAUGUUUAGGACCACUAGACCCGGCGGGCGCGGCGACAGCGA | 249 |
miR-204 | GGCUACAGUCUUUCUUCAUGUGACUCGUGGACUUCCCUUUGUCAUCCUAU GCCUGAGAAUAUAUGAAGGAGGCUGGGAAGGCAAAGGGACGUUCAAUUGUCAUCACUGGC | 250 |
miR-205 | AAAGAUCCUCAGACAAUCCAUGUGCUUCUCUUGUCCUUCAUUCCACCGGA GUCUGUCUCAUACCCAACCAGAUUUCAGUGGAGUGAAGUUCAGGAGGCAUGGAGCUGACA | 251 |
miR-206-1 | UGCUUCCCGAGGCCACAUGCUUCUUUAUAUCCCCAUAUGGAUUACUUUGCUAUGGAAUGUAAGGAAGUGUGUGGUUUCGGCAAGUG | 252 |
miR-206-2 | AGGCCACAUGCUUCUUUAUAUCCCCAUAUGGAUUACUUUGCUAUGGAAUG UAAGGAAGUGUGUGGUUUU | 253 |
miR-208 | UGACGGGCGAGCUUUUGGCCCGGGUUAUACCUGAUGCUCACGUAUAAGAC GAGCAAAAAGCUUGUUGGUCA | 254 |
miR-210 | ACCCGGCAGUGCCUCCAGGCGCAGGGCAGCCCCUGCCCACCGCACACUGCGCUGCCCCAGACCCACUGUGCGUGUGACAGCGGCUGAUCUGUGCCUGGGCAGCGCGACCC | 255 |
miR-211 | UCACCUGGCCAUGUGACUUGUGGGCUUCCCUUUGUCAUCCUUCGCCUAGGGCUCUGAGCAGGGCAGGGACAGCAAAGGGGUGCUCAGUUGUCACUUCCCACAGCACGGAG | 256 |
miR-212 | CGGGGCACCCCGCCCGGACAGCGCGCCGGCACCUUGGCUCUAGACUGCUUACUGCCCGGGCCGCCCUCAGUAACAGUCUCCAGUCACGGCCACCGACGCCUGGCCCCGCC | 257 |
miR-213-2 | CCUGUGCAGAGAUUAUUUUUUAAAAGGUCACAAUCAACAUUCAUUGCUGU CGGUGGGUUGAACUGUGUGGACAAGCUCACUGAACAAUGAAUGCAACUGUGGCCCCGCUU | 258 |
miR-213 | GAGUUUUGAGGUUGCUUCAGUGAACAUUCAACGCUGUCGGUGAGUUUGGAAUUAAAAUCAAAACCAUCGACCGUUGAUUGUACCCUAUGGCUAACCAUCAUCUACUCC | 259 |
miR-214 | GGCCUGGCUGGACAGAGUUGUCAUGUGUCUGCCUGUCUACACUUGCUGUGCAGAACAUCCGCUCACCUGUACAGCAGGCACAGACAGGCAGUCACAUGACAACCCAGCCU | 260 |
miR-215 | AUCAUUCAGAAAUGGUAUACAGGAAAAUGACCUAUGAAUUGACAGACAAUAUAGCUGAGUUUGUCUGUCAUUUCUUUAGGCCAAUAUUCUGUAUGACUGUGCUACUUCAA | 261 |
miR-216 | GAUGGCUGUGAGUUGGCUUAAUCUCAGCUGGCAACUGUGAGAUGUUCAUACAAUCCCUCACAGUGGUCUCUGGGAUUAUGCUAAACAGAGCAAUUUCCUAGCCCUCACGA | 262 |
miR-217 | AGUAUAAUUAUUACAUAGUUUUUGAUGUCGCAGAUACUGCAUCAGGAACU GAUUGGAUAAGAAUCAGUCACCAUCAGUUCCUAAUGCAUUGCCUUCAGCAUCUAAACAAG | 263 |
前体名称 | 序列(5′至3′)* | SEQ ID N0. |
miR-218-1 | GUGAUAAUGUAGCGAGAUUUUCUGUUGUGCUUGAUCUAACCAUGUGGUUGCGAGGUAUGAGUAAAACAUGGUUCCGUCAAGCACCAUGGAACGUCACGCAGCUUUCUACA | 264 |
miR-218-2 | GACCAGUCGCUGCGGGGCUUUCCUUUGUGCUUGAUCUAACCAUGUGGUGGAACGAUGGAAACGGAACAUGGUUCUGUCAAGCACCGCGGAAAGCACCGUGCUCUCCUGCA | 265 |
miR-219 | CCGCCCCGGGCCGCGGCUCCUGAUUGUCCAAACGCAAUUCUCGAGUCUAUGGCUCCGGCCGAGAGUUGAGUCUGGACGUCCCGAGCCGCCGCCCCCAAACCUCGAGCGGG | 266 |
miR-219-1 | CCGCCCCGGGCCGCGGCUCCUGAUUGUCCAAACGCAAUUCUCGAGUCUAUGGCUCCGGCCGAGAGUUGAGUCUGGACGUCCCGAGCCGCCGCCCCCAAACCUCGAGCGGG | 267 |
miR-219-2 | ACUCAGGGGCUUCGCCACUGAUUGUCCAAACGCAAUUCUUGUACGAGUCUGCGGCCAACCGAGAAUUGUGGCUGGACAUCUGUGGHCUGAGCUCCGGG | 268 |
miR-220 | GACAGUGUGGCAUUGUAGGGCUCCACACCGUAUCUGACACUUUGGGCGAGGGCACCAUGCUGAAGGUGUUCAUGAUGCGGUCUGGGAACUCCUCACGGAUCUUACUGAUG | 269 |
miR-221 | UGAACAUCCAGGUCUGGGGCAUGAACCUGGCAUACAAUGUAGAUUUCUGUGUUCGUUAGGCAACAGCUACAUUGUCUGCUGGGUUUCAGGCUACCUGGAAACAUGUUCUC | 270 |
miR-222 | GCUGCUGGAAGGUGUAGGUACCCUCAAUGGCUCAGUAGCCAGUGUAGAUCCUGUCUUUCGUAAUCAGCAGCUACAUCUGGCUACUGGGUCUCUGAUGGCAUCUUCUAGCU | 271 |
miR-223 | CCUGGCCUCCUGCAGUGCCACGCUCCGUGUAUUUGACAAGCUGAGUUGGACACUCCAUGUGGUAGAGUGUCAGUUUGUCAAAUACCCCAAGUGCGGCACAUGCUUACCAG | 272 |
miR-224 | GGGCUUUCAAGUCACUAGUGGUUCCGUUUAGUAGAUGAUUGUGCAUUGUUUCAAAAUGGUGCCCUAGUGACUACAAAGCCC | 273 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-294-1(chr16) | CAAUCUUCCUUUAUCAUGGUAUUGAUUUUUCAGUGCUUCCCUUUUGUGUGAGAGAAGAUA | 274 |
miR-296 | AGGACCCUUCCAGAGGGCCCCCCCUCAAUCCUGUUGUGCCUAAUUCAGAGGGUUGGGUGGAGGCUCUCCUGAAGGGCUCU | 275 |
miR-299 | AAGAAAUGGUUUACCGUCCCACAUACAUUUUGAAUAUGUAUGUGGGAUGGUAAACCGCUUCUU | 276 |
miR-301 | ACUGCUAACGAAUGCUCUGACUUUAUUGCACUACUGUACUUUACAGCUAGCAGUGCAAUAGUAUUGUCAAAGCAUCUGAAAGCAGG | 277 |
miR-302a | CCACCACUUAAACGUGGAUGUACUUGCUUUGAAACUAAAGAAGUAAGUGCUUCC AUGUUUUGGUGAUGG | 278 |
miR-302b | GCUCCCUUCAACUUUAACAUGGAAGUGCUUUCUGUGACUUUAAAAGUAAGUGCU UCCAUGUUUUAGUAGGAGU | 279 |
miR-302c | CCUUUGCUUUAACAUGGGGGUACCUGCUGUGUGAAACAAAAGUAAGUGCUUCCA UGUUUCAGUGGAGG | 280 |
miR-302d | CCUCUACUUUAACAUGGAGGCACUUGCUGUGACAUGACAAAAAUAAGUGCUUCC AUGUUUGAGUGUGG | 281 |
miR-320 | GCUUCGCUCCCCUCCGCCUUCUCUUCCCGGUUCUUCCCGGAGUCGGGAAAAGCU GGGUUGAGAGGGCGAAAAAGGAUGAGGU | 282 |
miR-321 | UUGGCCUCCUAAGCCAGGGAUUGUGGGUUCGAGUCCCACCCGGGGUAAAGAAAGGCCGA | 283 |
miR-323 | UUGGUACUUGGAGAGAGGUGGUCCGUGGCGCGUUCGCUUUAUUUAUGGCGCACAUUACACGGUCGACCUCUUUGCAGUAUCUAAUC | 284 |
miR-324 | CUGACUAUGCCUCCCCGCAUCCCCUAGGGCAUUGGUGUAAAGCUGGAGACCCAC UGCCCCAGGUGCUGCUGGGGGUUGUAGUC | 285 |
miR-325 | AUACAGUGCUUGGUUCCUAGUAGGUGUCCAGUAAGUGUUUGUGACAUAAUUUGUUUAUUGAGGACCUCCUAUCAAUCAAGCACUGUGCUAGGCUCUGG | 286 |
miR-326 | CUCAUCUGUCUGUUGGGCUGGAGGCAGGGCCUUUGUGAAGGCGGGUGGUGCUCAGAUCGCCUCUGGGCCCUUCCUCCAGCCCCGAGGCGGAUUCA | 287 |
miR-328 | UGGAGUGGGGGGGCAGGAGGGGCUCAGGGAGAAAGUGCAUACAGCCCCUGGCCC UCUCUGCCCUUCCGUCCCCUG | 288 |
miR-330 | CUUUGGCGAUCACUGCCUCUCUGGGCCUGUGUCUUAGGCUCUGCAAGAUCAACCGAGCAAAGCACACGGCCUGCAGAGAGGCAGCGCUCUGCCC | 289 |
miR-331 | GAGUUUGGUUUUGUUUGGGUUUGUUCUAGGUAUGGUCCCAGGGAUCCCAGAUCAAACCAGGCCCCUGGGCCUAUCCUAGAACCAACCUAAGCUC | 290 |
miR-335 | UGUUUUGAGCGGGGGUCAAGAGCAAUAACGAAAAAUGUUUGUCAUAAACCGUUUUUCAUUAUUGCUCCUGACCUCCUCUCAUUUGCUAUAUUCA | 291 |
miR-337 | GUAGUCAGUAGUUGGGGGGUGGGAACGGCUUCAUACAGGAGUUGAUGCACAGUUAUCCAGCUCCUAUAUGAUGCCUUUCUUCAUCCCCUUCAA | 292 |
miR-338 | UCUCCAACAAUAUCCUGGUGCUGAGUGAUGACUCAGGCGACUCCAGCAUCAGUG AUUUUGUUGAAGA | 293 |
miR-339 | CGGGGCGGCCGCUCUCCCUGUCCUCCAGGAGCUCACGUGUGCCUGCCUGUGAGCGCCUCGACGACAGAGCCGGCGCCUGCCCCAGUGUCUGCGC | 294 |
前体名称 | 序列(5′至3′)* | SEQ ID NO. |
miR-340 | UUGUACCUGGUGUGAUUAUAAAGCAAUGAGACUGAUUGUCAUAUGUCGUUUGUGGGAUCCGUCUCAGUUACUUUAUAGCCAUACCUGGUAUCUUA | 295 |
miR-342 | GAAACUGGGCUCAAGGUGAGGGGUGCUAUCUGUGAUUGAGGGACAUGGUUAAUGGAAUUGUCUCACACAGAAAUCGCACCCGUCACCUUGGCCUACUUA | 296 |
miR-345 | ACCCAAACCCUAGGUCUGCUGACUCCUAGUCCAGGGCUCGUGAUGGCUGGUGGGCCCUGAACGAGGGGUCUGGAGGCCUGGGUUUGAAUAUCGACAGC | 297 |
miR-346 | GUCUGUCUGCCCGCAUGCCUGCCUCUCUGUUGCUCUGAAGGAGGCAGGGGCUGGGCCUGCAGCUGCCUGGGCAGAGCGGCUCCUCC | 298 |
miR-367 | CCAUUACUGUUGCUAAUAUGCAACUCUGUUGAAUAUAAAUUGGAAUUGCACUUUACCAAUGGUGAUGG | 299 |
miR-368 | AAAAGGUGGAUAUUCCUUCUAUGUUUAUGUUAUUUAUGGUUAAACAUAGAGGAA AUUCCACGUUUU | 300 |
miR-369 | UUGAAGGGAGAUCGACCGUGUUAUAUUCGCUUUAUUGACUUCGAAUAAUACAUG GUUGAUCUUUUCUCAG | 301 |
miR-370 | AGACAGAGAAGCCAGGUCACGUCUCUGCAGUUACACAGCUCACGAGUGCCUGCU GGGGUGGAACCUGGUCUGUCU | 302 |
miR-371 | GUGGCACUCAAACUGUGGGGGCACUUUCUGCUCUCUGGUGAAAGUGCCGCCAUC UUUUGAGUGUUAC | 303 |
miR-372 | GUGGGCCUCAAAUGUGGAGCACUAUUCUGAUGUCCAAGUGGAAAGUGCUGCGAC AUUUGAGCGUCAC | 304 |
miR-373 | GGGAUACUCAAAAUGGGGGCGCUUUCCUUUUUGUCUGUACUGGGAAGUGCUUCGAUUUUGGGGUGUCCC | 305 |
miR-374 | UACAUCGGCCAUUAUAAUACAACCUGAUAAGUGUUAUAGCACUUAUCAGAUUGUAUUGUAAUUGUCUGUGUA | 306 |
miR-hes1 | AUGGAGCUGCUCACCCUGUGGGCCUCAAAUGUGGAGGAACUAUUCUGAUGUCCAAGUGGAAAGUGCUGCGACAUUUGAGCGUCACCGGUGACGCCCAUAUCA | 307 |
miR-hes2 | GCAUCCCCUCAGCCUGUGGCACUCAAACUGUGGGGGCACUUUCUGCUCUCUGGUGAAAGUGCCGCCAUCUUUUGAGUGUUACCGCUUGAGAAGACUCAACC | 308 |
miR-hes3 | CGAGGAGCUCAUACUGGGAUACUCAAAAUGGGGGCGCUUUCCUUUUUGUCUGUUACUGGGAAGUGCUUCGAUUUUGGGGUGUCCCUGUUUGAGUAGGGCAUC | 309 |
*前体序列中加下划线的序列对应着成熟的加工过的miR转录物(参见表1b)。有些前体序列具有2个加下划线的序列,它们表示源自相同前体的2种不同的成熟miR。所有序列都是人的。
表1b-人成熟微小RNA序列
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
let-7a | ugagguaguagguuguauaguu | 310 | let-7a-1;let-7a-2;let-7a-3;let-7a-4 |
let-7b | ugagguaguagguugugugguu | 311 | let-7b |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
let-7c | ugagguaguagguuguaugguu | 312 | let-7c |
let-7d | agagguaguagguugcauagu | 313 | let-7d;let-7d-v1 |
let-7e | ugagguaggagguuguauagu | 314 | let-7e |
let-7f | ugagguaguagauuguauaguu | 315 | let-7f-1;let-7f-2-1;let-7f-2-2 |
let-7g | ugagguaguaguuuguacagu | 316 | let-7g |
let-7i | ugagguaguaguuugugcu | 317 | let-7i |
miR-1 | uggaauguaaagaaguaugua | 318 | miR-1b;miR-1b-1;miR-1b-2 |
miR-7 | uggaagacuagugauuuuguu | 319 | miR-7-1;miR-7-1a;miR-7-2;miR-7-3 |
miR-9 | ucuuugguuaucuagcuguauga | 320 | miR-9-1;miR-9-2;miR-9-3 |
miR-9* | uaaagcuagauaaccgaaagu | 321 | miR-9-1;miR-9-2;miR-9-3 |
miR-10a | uacccuguagauccgaauuugug | 322 | miR-10a |
miR-10b | uacccuguagaaccgaauuugu | 323 | miR-10b |
miR-15a | uagcagcacauaaugguuugug | 324 | miR-15a;miR-15a-2 |
miR-15b | uagcagcacaucaugguuuaca | 325 | miR-15b |
miR-16 | uagcagcacguaaauauuggcg | 326 | miR-16-1;miR-16-2;miR-16-13 |
miR-17-5p | caaagugcuuacagugcagguagu | 327 | miR-17 |
miR-17-3p | acugcagugaaggcacuugu | 328 | miR-17 |
miR-18 | uaaggugcaucuagugcagaua | 329 | miR-18;miR-18-13 |
miR-19a | ugugcaaaucuaugcaaaacuga | 330 | miR-19a;miR-19a-13 |
miR-19b | ugugcaaauccaugcaaaacuga | 331 | miR-19b-1;miR-19b-2 |
miR-20 | uaaagugcuuauagugcaggua | 332 | miR-20(miR-20a) |
miR-21 | uagcuuaucagacugauguuga | 333 | miR-21;miR-21-17 |
miR-22 | aagcugccaguugaagaacugu | 334 | miR-22 |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-23a | aucacauugccagggauuucc | 335 | miR-23a |
miR-23b | aucacauugccagggauuaccac | 336 | miR-23b |
miR-24 | uggcucaguucagcaggaacag | 337 | miR-24-1;miR-24-2;miR-24-19;miR-24-9 |
miR-25 | cauugcacuugucucggucuga | 338 | miR-25 |
miR-26a | uucaaguaauccaggauaggcu | 339 | miR-26a;miR-26a-1;miR-26a-2 |
miR-26b | uucaaguaauucaggauaggu | 340 | miR-26b |
miR-27a | uucacaguggcuaaguuccgcc | 341 | miR-27a |
miR-27b | uucacaguggcuaaguucug | 342 | miR-27b-1;miR-27b-2 |
miR-28 | aaggagcucacagucuauugag | 343 | miR-28 |
miR-29a | cuagcaccaucugaaaucgguu | 344 | miR-29a-2;miR-29a |
miR-29b | uagcaccauuugaaaucagu | 345 | miR-29b-1;miR-29b-2 |
miR-29c | uagcaccauuugaaaucgguua | 346 | miR-29c |
miR-30a-5p | uguaaacauccucgacuggaagc | 347 | miR-30a |
miR-30a-3p | cuuucagucggauguuugcagc | 348 | miR-30a |
miR-30b | uguaaacauccuacacucagc | 349 | miR-30b-1;miR-30b-2 |
miR-30c | uguaaacauccuacacucucagc | 350 | miR-30c |
miR-30d | uguaaacauccccgacuggaag | 351 | miR-30d |
miR-30e | uguaaacauccuugacugga | 352 | miR-30e |
miR-31 | ggcaagaugcuggcauagcug | 353 | miR-31 |
miR-32 | uauugcacauuacuaaguugc | 354 | miR-32 |
miR-33 | gugcauuguaguugcauug | 355 | miR-33;miR-33b |
miR-34a | uggcagugucuuagcugguugu | 356 | miR-34a |
miR-34b | aggcagugucauuagcugauug | 357 | miR-34b |
miR-34c | aggcaguguaguuagcugauug | 358 | miR-34c |
miR-92 | uauugcacuugucccggccugu | 359 | miR-92-2;miR-92-1 |
miR-93 | aaagugcuguucgugcagguag | 360 | miR-93-1;miR-93-2 |
miR-95 | uucaacggguauuuauugagca | 361 | miR-95 |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-96 | uuuggcacuagcacauuuuugc | 362 | miR-96 |
miR-98 | ugagguaguaaguuguauuguu | 363 | miR-98 |
miR-99a | aacccguagauccgaucuugug | 364 | miR-99a |
miR-99b | cacccguagaaccgaccuugcg | 365 | miR-99b |
miR-100 | uacaguacugugauaacugaag | 366 | miR-100 |
miR-101 | uacaguacugugauaacugaag | 367 | miR-101-1;miR-101-2 |
miR-103 | agcagcauuguacagggcuauga | 368 | miR-103-1 |
miR-105 | ucaaaugcucagacuccugu | 369 | miR-105 |
miR-106-a | aaaagugcuuacagugcagguagc | 370 | miR-106-a |
miR-106-b | uaaagugcugacagugcagau | 371 | miR-106-b |
miR-107 | agcagcauuguacagggcuauca | 372 | miR-107 |
miR-122a | uggagugugacaaugguguuugu | 373 | miR-122a-1;miR-122a-2 |
miR-124a | uuaaggcacgcggugaaugcca | 374 | miR-124a-1;miR-124a-2;miR-124a-3 |
miR-125a | ucccugagacccuuuaaccugug | 375 | miR-125a-1;miR-125a-2 |
miR-125b | ucccugagacccuaacuuguga | 376 | miR-125b-1;miR-125b-2 |
miR-126* | cauuauuacuuuugguacgcg | 377 | miR-126-1;miR-126-2 |
miR-126 | ucguaccgugaguaauaaugc | 378 | miR-126-1;miR-126-2 |
miR-127 | ucggauccgucugagcuuggcu | 379 | miR-127-1;miR-127-2 |
miR-128a | ucacagugaaccggucucuuuu | 380 | miR-128;miR-128a |
miR-128b | ucacagugaaccggucucuuuc | 381 | miR-128b |
miR-129 | cuuuuugcggucugggcuugc | 382 | miR-129-1;miR-129-2 |
miR-130a | cagugcaauguuaaaagggc | 383 | miR-130a |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-130b | cagugcaaugaugaaagggcau | 384 | miR-130b |
miR-132 | uaacagucuacagccauggucg | 385 | miR-132-1 |
miR-133a | uugguccccuucaaccagcugu | 386 | miR-133a-1;miR-133a-2 |
miR-133b | uugguccccuucaaccagcua | 387 | miR-133b |
miR-134 | ugugacugguugaccagaggg | 388 | miR-134-1;miR-134-2 |
miR-135a | uauggcuuuuuauuccuauguga | 389 | miR-135a;miR-135a-2(miR-135-2) |
miR-135b | uauggcuuuucauuccuaugug | 390 | miR-135b |
miR-136 | acuccauuuguuuugaugaugga | 391 | miR-136-1;miR-136-2 |
miR-137 | uauugcuuaagaauacgcguag | 392 | miR-137 |
miR-138 | agcugguguugugaauc | 393 | miR-138-1;miR-138-2 |
miR-139 | ucuacagugcacgugucu | 394 | miR-139 |
miR-140 | agugguuuuacccuaugguag | 395 | miR-140;miR-140as;miR-140s |
miR-141 | aacacugucugguaaagaugg | 396 | miR-141-1;miR-141-2 |
miR-142-3p | uguaguguuuccuacuuuaugga | 397 | miR-142 |
miR-142-5p | cauaaaguagaaagcacuac | 398 | miR-142 |
miR-143 | ugagaugaagcacuguagcuca | 399 | miR-143-1 |
miR-144 | uacaguauagaugauguacuag | 400 | miR-144-1;miR-144-2 |
miR-145 | guccaguuuucccaggaaucccuu | 401 | miR-145-1;miR-145-2 |
miR-146 | ugagaacugaauuccauggguu | 402 | miR-146-1;miR-146-2 |
miR-147 | guguguggaaaugcuucugc | 403 | miR-147 |
miR-148a | ucagugcacuacagaacuuugu | 404 | miR-148a(miR-148) |
miR-148b | ucagugcaucacagaacuuugu | 405 | miR-148b |
miR-149 | ucuggcuccgugucuucacucc | 406 | miR-149 |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-150 | ucucccaacccuuguaccagug | 407 | miR-150-1;miR-150-2 |
miR-151 | acuagacugaagcuccuugagg | 408 | miR-151 |
miR-152 | ucagugcaugacagaacuugg | 409 | miR-152-1;miR-152-2 |
miR-153 | uugcauagucacaaaaguga | 410 | miR-153-1-1;miR-153-1-2;miR-153-2-1;miR-153-2-2 |
miR-154 | uagguuauccguguugccuucg | 411 | miR-154-1;miR-154-2 |
miR-154* | aaueauaeaegguugaccuauu | 412 | miR-154-1;miR-154-2 |
miR-155 | uuaaugcuaaucgugauagggg | 413 | miR-155 |
miR-181a | aacauucaacgcugucggugagu | 414 | miR-181a |
miR-181b | aacauucauugcugucgguggguu | 415 | miR-181b-1;miR-181b-2 |
miR-181c | aacauucaaccugucggugagu | 416 | miR-181c |
miR-182 | uuuggcaaugguagaacucaca | 417 | miR-182;miR-182as |
miR-182* | ugguucuagacuugccaacua | 418 | miR-182;miR-182as |
miR-183 | uauggcacugguagaauucacug | 419 | miR-183 |
miR-184 | uggacggagaacugauaagggu | 420 | miR-184-1;miR-184-2 |
miR-185 | uggagagaaaggcaguuc | 421 | miR-185-1;miR-185-2 |
miR-186 | caaagaauucuccuuuugggcuu | 422 | miR-186-1;miR-186-2 |
miR-187 | ucgugucuuguguugcagccg | 423 | miR-187 |
miR-188 | caucccuugcaugguggagggu | 424 | miR-188 |
miR-189 | gugccuacugagcugauaucagu | 425 | miR-189-1;miR-189-2 |
miR-190 | ugauauguuugauauauuaggu | 426 | miR-190-1;miR-190-2 |
miR-191 | caacggaaucccaaaagcagcu | 427 | miR-191-1;miR-191-2 |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-192 | cugaccuaugaauugacagcc | 428 | miR-192 |
miR-193 | aacuggccuacaaagucccag | 429 | miR-193-1;miR-193-2 |
miR-194 | uguaacagcaacuccaugugga | 430 | miR-194-1;miR-194-2 |
miR-195 | uagcagcacagaaauauuggc | 431 | miR-195-1;miR-195-2 |
miR-196a | uagguaguuucauguuguugg | 432 | miR-196a;miR-196a-2(miR196-2) |
miR-196b | uagguaguuuccuguuguugg | 433 | miR-196b |
miR-197 | uueaeeaccuucuccacccagc | 434 | miR-197 |
miR-198 | gguccagaggggagauagg | 435 | miR-198 |
miR-199a | cccaguguucagacuaccuguuc | 436 | miR-199a-1;miR-199a-2 |
miR-199a* | uacaguagucugcacauugguu | 437 | miR-199a-1;miR-199a-2;miR-199s;miR-199b |
miR-199b | cccaguguuuagacuaucuguuc | 438 | miR-199b |
miR-200a | uaacacugucugguaacgaugu | 439 | miR-200a |
miR-200b | cucuaauacugccugguaaugaug | 440 | miR-200b |
miR-200c | aauacugccggguaaugaugga | 441 | miR-200c |
miR-202 | agagguauagggcaugggaaga | 442 | miR-202 |
miR-203 | gugaaauguuuaggaccacuag | 443 | miR-203 |
miR-204 | uucccuuugucauccuaugccu | 444 | miR-204 |
miR-205 | uccuucauuccaccggagucug | 445 | miR-205 |
miR-206 | uggaauguaaggaagugugugg | 446 | miR-206-1;miR-206-2 |
miR-208 | auaagacgagcaaaaagcuugu | 447 | miR-208 |
miR-210 | cugugcgugugacagcggcug | 448 | miR-210 |
miR-211 | uucccuuugucauccuucgccu | 449 | miR-2i1 |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-212 | uaacagucuccagucacggcc | 450 | miR-212 |
miR-213 | accaucgaccguugauuguacc | 451 | miR-213 |
miR-214 | acagcaggcacagacaggcag | 452 | miR-214 |
miR-215 | augaccuaugaauugacagac | 453 | miR-215 |
miR-216 | uaaucucagcuggcaacugug | 454 | miR-216 |
miR-217 | uacugcaucaggaacugauuggau | 455 | miR-217 |
miR-218 | uugugcuugaucuaaccaugu | 456 | miR-218-1;miR-218-2 |
miR-219 | ugauuguccaaacgcaauucu | 457 | miR-219;miR-219-1;miR-219-2 |
miR-220 | ccacaccguaucugacacuuu | 458 | miR-220 |
miR-221 | agcuacauugucugcuggguuuc | 459 | miR-221 |
miR-222 | agcuacaucuggcuacugggucuc | 460 | miR-222 |
miR-223 | ugucaguuugucaaauacccc | 461 | miR-223 |
miR-224 | caagucacuagugguuccguuua | 462 | miR-224 |
miR-296 | agggcccccccucaauccugu | 463 | miR-296 |
miR-299 | ugguuuaccgucccacauacau | 464 | miR-299 |
miR-301 | cagugcaauaguauugucaaagc | 465 | miR-301 |
miR-302a | uaagugcuuccauguuuugguga | 466 | miR-302a |
miR-302b* | acuuuaacauggaagugcuuucu | 467 | miR-302b |
miR-302b | uaagugcuuccauguuuuaguag | 468 | miR-302b |
miR-302c* | uuuaacauggggguaccugcug | 469 | miR-302c |
miR-302c | uaagugcuuccauguuucagugg | 470 | miR-302c |
miR-302d | uaagugcuuccauguuugagugu | 471 | miR-302d |
miR-320 | aaaagcuggguugagagggcgaa | 472 | miR-320 |
miR-321 | uaagccagggauuguggguuc | 473 | miR-321 |
miR-323 | gcacauuacacggucgaccucu | 474 | miR-323 |
miR-324-5p | cgcauccccuagggcauuggugu | 475 | miR-324 |
miR-324-3p | ccacugccccaggugcugcugg | 476 | miR-324 |
miR-325 | ccuaguagguguccaguaagu | 477 | miR-325 |
miR-326 | ccucugggcccuuccuccag | 478 | miR-326 |
miR-328 | cuggcccucucugcccuuccgu | 479 | miR-328 |
成熟miRNA名称 | 成熟miRNA序列(5′至3′) | SEQ ID NO. | 相应的前体微小RNA;参见表1a |
miR-330 | gcaaagcacacggccugcagaga | 480 | miR-330 |
miR-331 | gccccugggccuauccuagaa | 481 | miR-331 |
miR-335 | ucaagagcaauaacgaaaaaugu | 482 | miR-335 |
miR-337 | uccagcuccuauaugaugccuuu | 483 | miR-337 |
miR-338 | uccagcaucagugauuuuguuga | 484 | miR-338 |
miR-339 | ucccuguccuccaggagcuca | 485 | miR-339 |
miR-340 | uccgucucaguuacuuuauagcc | 486 | miR-340 |
miR-342 | ucucacacagaaaucgcacccguc | 487 | miR-342 |
miR-345 | ugcugacuccuaguccagggc | 488 | miR-345 |
miR-346 | ugucugcccgcaugccugccucu | 489 | miR-346 |
miR-367 | aauugcacuuuagcaaugguga | 490 | miR-367 |
miR-368 | acauagaggaaauuccacguuu | 491 | m1R-368 |
miR-369 | aauaauacaugguugaucuuu | 492 | miR-369 |
miR-370 | gccugcugggguggaaccugg | 493 | miR-370 |
miR-371 | gugccgccaucuuuugagugu | 494 | miR-371 |
miR-372 | aaagugcugcgacauuugagcgu | 495 | miR-372 |
miR-373* | acucaaaaugggggcgcuuucc | 496 | miR-373 |
miR-373 | gaagugcuucgauuuuggggugu | 497 | miR-373 |
miR-374 | uuauaauacaaccugauaagug | 498 | miR-374 |
本发明包括诊断受试者是否患有实体癌或处于发生实体癌的风险中的方法,该方法包括测量来自受试者的测试样品中的至少一种miR基因产物的水平,和将测试样品中的miR基因产物的水平与对照样品中相应的miR基因产物的水平进行比较。如本文所用的,“受试者”可以是患有或怀疑患有实体癌的任何哺乳动物。在一个优选的实施方案中,受试者是患有或怀疑患有实体癌的人。
在一个实施方案中,在测试样品中测量的至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。在一个特定的实施方案中,所述miR基因产物是miR-21,miR-191或miR-17-5p。在另一个实施方案中,所述miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,1et-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述miR基因产物不是miR-15a,miR-16-1,miR-182,miR-181,miR-30,miR-15a,miR-16-1,miR-15b,miR-16-2,miR-195,miR-34,miR-153,miR-21,miR-217,miR-205,miR-204,miR-211,miR-143,miR-96,miR-103,miR-107,miR-129,miR-9,miR-137,miR-217,miR-186。
所述实体癌可以是源自器官和实体组织的任意癌症。这样的癌症通常伴随肿瘤块的形成和/或存在,可以是癌、肉瘤和淋巴瘤。要通过本发明的方法诊断的实体癌的特定实例包括、但不限于,结肠癌,直肠癌,胃癌,胰腺癌,乳腺癌,肺癌,前列腺癌,支气管癌,睾丸癌,卵巢癌,子宫癌,阴茎癌,黑素瘤和其它皮肤癌,肝癌,食道癌,口腔和咽癌(例如舌癌,口腔癌),消化系统癌(例如肠癌,胆囊癌),骨和关节癌,内分泌系统癌(例如甲状腺癌),脑癌,眼癌,泌尿系统癌(例如肾癌,膀胱癌),霍奇金病和非霍奇金淋巴瘤。在具体实施方案中,所述实体癌不是下述的一种或多种:乳腺癌,肺癌,前列腺癌,胰腺癌或胃肠癌。
在一个实施方案中,所述实体癌是乳腺癌或肺癌,且在测试样品中测量的至少一种miR基因产物选自:miR-210,miR-213和其组合。
在另一个实施方案中,所述实体癌是结肠癌,胃癌,前列腺癌或胰腺癌,且在测试样品中测量的至少一种miR基因产物是miR-218-2。
在本发明的一个特定实施方案中,所述实体癌是乳腺癌,且在测试样品中测量的至少一种miR基因产物选自:miR-125b-1,miR-125b-2,miR-145,miR-21和其组合。在一个相关实施方案中,所述实体癌是乳腺癌,且测试样品中的至少一种miR基因产物选自:miR-21,miR-29b-2,miR-146,miR-125b-2,miR-125b-1,miR-10b,miR-145,miR-181a,miR-140,miR-213,miR-29a prec,miR-181b-1,miR-199b,miR-29b-1,miR-130a,miR-155,let-7a-2,miR-205,miR-29c,miR-224,miR-100,miR-31,miR-30c,miR-17-5p,miR-210,miR-122a,miR-16-2和其组合。在一个相关实施方案中,所述实体癌是乳腺癌,且所述至少一种miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述实体癌是乳腺癌,且所述至少一种miR基因产物不是miR-145,miR-21,miR-155,miR-10b,miR-125b-1,miR-125b-2,let7a-2,let7a-3,let-7d,miR-122a,miR-191,miR-206,miR-210,let-7i,miR-009-1(miR131-1),miR-34(miR-170),miR-102(miR-29b),miR-123(miR-126),miR-140-as,miR-125a,miR-194,miR-204,miR-213,let-7f-2,miR-101,miR-128b,miR-136,miR-143,miR-149,miR-191,miR-196-1,miR-196-2,miR-202,miR-103-1,或miR-30c。在另一个实施方案中,所述实体癌是乳腺癌,且所述miR基因产物不是miR-21,miR-125b-1,let-7a-2,let-7i,miR-100,let-7g,miR-31,miR-32a-1,miR-33b,miR-34a-2,miR-101-1,miR-135-1,miR-142as,miR-142s,miR-144,miR-301,miR-29c,miR-30c,miR-106a,或miR-29b-1。在另一个实施方案中,所述实体癌是乳腺癌,且所述miR基因产物不是miR-159-1或miR-192。在另一个实施方案中,所述实体癌是乳腺癌,且所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述实体癌是乳腺癌,且所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述实体癌是乳腺癌,且所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述实体癌是乳腺癌,且所述miR基因产物不是miR-181b,miR-181c,miR-181d,miR-30,miR-15b,miR-16-2,miR-153-1,miR-217,miR-205,miR-204,miR-103,miR-107,miR-129-2,miR-9或miR-137。
在另一个实施方案中,所述实体癌是结肠癌,且测试样品中的至少一种miR基因产物选自:miR-24-1,miR-29b-2,miR-20a,miR-10a,miR-32,miR-203,miR-106a,miR-17-5p,miR-30c,miR-223,miR-126*,miR-128b,miR-21,miR-24-2,miR-99bprec,miR-155,miR-213,miR-150,miR-107,miR-191,miR-221,miR-9-3和其组合。在另一个实施方案中,所述实体癌是结肠癌,且所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述实体癌是结肠癌,且所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述实体癌是结肠癌,且所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述实体癌是结肠癌,且所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述实体癌是结肠癌,且所述miR基因产物不是miR-181b,miR-181c,miR-181d,miR-30,miR-15b,miR-16-2,miR-153-1,miR-217,miR-205,miR-204,miR-103,miR-107,miR-129-2,miR-9或miR-137。
在另一个实施方案中,所述实体癌是肺癌,且测试样品中的miR基因产物选自:miR-21,miR-205,miR-200b,miR-9-1,miR-210,miR-148,miR-141,miR-132,miR-215,miR-128b,let-7g,miR-16-2,miR-129-1/2prec,miR-126*,miR-142-as,miR-30d,miR-30a-5p,miR-7-2,miR-199a-1,miR-127,miR-34aprcc,miR-34a,miR-136,miR-202,miR-196-2,miR-199a-2,let-7a-2,miR-124a-1,miR-149,miR-17-5p,miR-196-1 prec,miR-10a,miR-99b prec,miR-196-1,miR-199b,miR-191,miR-195,miR-155和其组合。在一个相关实施方案中,所述实体癌是肺癌,且所述至少一种miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述实体癌是肺癌,且所述至少一种miR基因产物不是miR-21,miR-191,miR-126*,miR-210,miR-155,miR-143,miR-205,miR-126,miR-30a-5p,miR-140,miR-214,miR-218-2,miR-145,miR-106a,miR-192,miR-203,miR-150,miR-220,miR-192,miR-224,miR-24-2,miR-212,miR-9,miR-17,miR-124a-1,miR-95,miR-198,miR-216,miR-219-1,miR-197,miR-125a,miR-26a-1,miR-146,miR-199b,let7a-2,miR-27b,miR-32,miR-29b-2,miR-33,miR-181c,miR-101-1,miR-124a-3,miR-125b-1或let7f-1。在另一个实施方案中,所述实体癌是肺癌,且所述至少一种miR基因产物不是miR-21,miR-182,miR-181,miR-30,miR-15a,miR-143,miR-205,miR-96,miR-103,miR-107,miR-129,miR-137,miR-186,miR-15b,miR-16-2,miR-195,miR-34,miR-153,miR-217,miR-204,miR-211,miR-9,miR-217,let-7a-2或miR-32。在另一个实施方案中,所述实体癌是肺癌,且所述miR基因产物不是let-7c,let-7g,miR-7-3,miR-210,miR-31,miR-34a-1,miR-a-2,miR-99a,miR-100,miR-125b-2,miR-132,miR-135-1,miR-195,miR-34,miR-123,miR-203。在另一个实施方案中,所述实体癌是肺癌,且所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述实体癌是肺癌,且所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述实体癌是肺癌,且所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述实体癌是肺癌,且所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,1et-7a,1et-7f,或let-7d。在另一个实施方案中,所述实体癌是肺癌,且所述miR基因产物不是miR-181b,miR-181c,miR-181d,miR-30,miR-15b,miR-16-2,miR-153-1,miR-217,miR-205,miR-204,miR-103,miR-107,miR-129-2,miR-9或miR-137。
在另一个实施方案中,所述实体癌是胰腺癌,且在测试样品中测量的至少一种miR基因产物选自:miR-103-1,miR-103-2,miR-155,miR-204和其组合。在一个相关实施方案中,所述实体癌是胰腺癌,且测试样品中的miR基因产物选自:miR-103-2,miR-103-1,miR-24-2,miR-107,miR-100,miR-125b-2,miR-125b-1,miR-24-1,miR-191,miR-23a,miR-26a-1,miR-125a,miR-130a,miR-26b,miR-145,miR-221,miR-126*,miR-16-2,miR-146,miR-214,miR-99b,miR-128b,miR-155,miR-29b-2,miR-29a,miR-25,miR-16-1,miR-99a,miR-224,miR-30d,miR-92-2,miR-199a-1,miR-223,miR-29c,miR-30b,miR-129-1/2,miR-197,miR-17-5p,miR-30c,miR-7-1,miR-93-1,miR-140,miR-30a-5p,miR-132,miR-181b-1,miR-152prec,miR-23b,miR-20a,miR-222,miR-27a,miR-92-1,miR-21,miR-129-1/2 prec,miR-150,miR-32,miR-106a,miR-29b-1和其组合。在一个实施方案中,所述实体癌是胰腺癌,且所述miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述实体癌是胰腺癌,且所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述实体癌是胰腺癌,且所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述实体癌是胰腺癌,且所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述实体癌是胰腺癌,且所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述实体癌是胰腺癌,且所述miR基因产物不是miR-181b,miR-181c,miR-181d,miR-30,miR-15b,miR-16-2,miR-153-1,miR-217,miR-205,miR-204,miR-103,miR-107,miR-129-2,miR-9或miR-137。
在另一个实施方案中,所述实体癌是前列腺癌,且测试样品中的miR基因产物选自:let-7d,miR-128a prec,miR-195,miR-203,let-7a-2 prec,miR-34a,miR-20a,miR-218-2,miR-29a,miR-25,miR-95,miR-197,miR-135-2,miR-187,miR-196-1,miR-148,miR-191,miR-21,let-7i,miR-198,miR-199a-2,miR-30c,miR-17-5p,miR-92-2,miR-146,miR-181b-1prec,miR-32,miR-206,miR-184prec,miR-29a prec,miR-29b-2,miR-149,miR-181b-1,miR-196-1prec,miR-93-1,miR-223,miR-16-1,miR-101-1,miR-124a-1,miR-26a-1,miR-214,miR-27a,miR-24-1,miR-106a,miR-199a-1和其组合。在一个相关实施方案中,所述实体癌是前列腺癌,且所述miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述实体癌是前列腺癌,且所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述实体癌是前列腺癌,且所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,1et-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述实体癌是前列腺癌,且所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述实体癌是前列腺癌,且所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述实体癌是前列腺癌,且所述miR基因产物不是miR-181b,miR-181c,miR-181d,miR-30,miR-15b,miR-16-2,miR-153-1,miR-217,miR-205,miR-204,miR-103,miR-107,miR-129-2,miR-9或miR-137。
在另一个实施方案中,所述实体癌是胃癌,且测试样品中的miR基因产物选自:miR-223,miR-21,miR-218-2,miR-103-2,miR-92-2,miR-25,miR-136,miR-191,miR-221,miR-125b-2,miR-103-1,miR-214,miR-222,miR-212 prec,miR-125b-1,miR-100,miR-107,miR-92-1,miR-96,miR-192,miR-23a,miR-215,miR-7-2,miR-138-2,miR-24-1,miR-99b,miR-33b,miR-24-2和其组合。在一个相关实施方案中,所述实体癌是胃癌,且所述miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述实体癌是胃癌,且所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述实体癌是胃癌,且所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,1et-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述实体癌是胃癌,且所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述实体癌是胃癌,且所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述实体癌是胃癌,且所述miR基因产物不是miR-181b,miR-181c,miR-181d,miR-30,miR-15b,miR-16-2,miR-153-1,miR-217,miR-205,miR-204,miR-103,miR-107,miR-129-2,miR-9或miR-137。
可以测量从受试者得到的生物样品(例如细胞,组织)中的至少一种miR基因产物的水平。例如,通过常规活组织检查技术,可以从被怀疑患有实体癌的受试者取出组织样品(例如来自肿瘤)。在另一个实施方案中,可以从受试者取出血液样品,并可通过标准技术,分离血细胞(例如白细胞)用于DNA提取。优选地,在放疗、化疗或其它治疗性处理开始之前,从受试者得到血液或组织样品。相应的对照组织或血液样品可以从受试者的未受影响的组织、从正常人个体或正常个体的群体、或从与受试者样品中大多数细胞相对应的培养细胞得到。然后与来自受试者的样品一起,加工处理对照组织或血液样品,从而可以将来自受试者样品的细胞中从给定miR基因产生的miR基因产物的水平与来自对照样品的细胞的相应miR基因产物水平相对比。也可以将生物样品的参照miR表达标准用作对照。
与对照样品中的相应的miR基因产物的水平相比,从受试者得到的样品中miR基因产物的水平的改变(即,增加或降低),指示着在受试者中存在实体癌。在一个实施方案中,测试样品中至少一种miR基因产物的水平大于对照样品中的相应的miR基因产物的水平(即,miR基因产物的表达被“增量调节”)。如本文使用的,当来自受试者的细胞或组织样品中miR基因产物的量大于对照细胞或组织样品中相同基因产物的量时,该miR基因产物的表达被"增量调节"。在另一个实施方案中,测试样品中至少一种miR基因产物的水平小于对照样品中的相应的miR基因产物的水平(即,miR基因产物的表达被"减量调节")。如本文使用的,当从来自受试者的细胞或组织样品的基因产生的miR基因产物的量小于从对照细胞或组织样品中相同基因产生的量时,该miR基因产物的表达被"减量调节"。可以想对于一种或多种RNA表达标准,测定对照和正常样品中的相对miR基因表达。所述标准包含,例如,零miR基因表达水平,标准细胞系中的miR基因表达水平,受试者的未受影响的组织中miR基因表达水平,或以前对正常人对照群体得到的miR基因表达的平均水平。
使用适用于检测生物样品中的RNA表达水平的任意技术,可以测量样品中miR基因产物的水平。用于测定生物样品(例如,细胞,组织)中RNA表达水平的合适技术(例如,RNA印迹分析,RT-PCR,原位杂交)是本领域技术人员众所周知的。在一个具体的实施方案中,使用RNA印迹分析,检测至少一种miR基因产物的水平。例如,可以如下从细胞纯化总细胞RNA:在有核酸提取缓冲液存在下匀浆,随后离心。沉淀核酸,通过用DNA酶处理和沉淀,去除DNA。然后根据标准技术,通过琼脂糖凝胶上的凝胶电泳分离RNA分子,并转移至硝酸纤维素滤膜。然后通过加热,将RNA固定化在滤膜上。使用与目标RNA互补的适当标记的DNA或RNA探针,进行对特定RNA的检测和定量。参见,例如,Molecular Cloning:A Laboratory Manual,J.Sambrook等人编,第2版,ColdSpring Harbor Laboratory Press,1989,Chapter7,其所有公开内容通过参考引用并入本文。
从表1a和表1b中提供的核酸序列,可以生成用于给定miR基因产物的RNA印迹杂交的合适探针,包括、但不限于,与目标miR基因产物具有至少约70%、75%、80%、85%、90%、95%、98%、99%或完全互补性的探针。标记的DNA和RNA探针的制备方法,和其与靶核苷酸序列的杂交的条件,描述在Molecular Cloning:A Laboratory Manual,J.Sambrook等人编,第2版,Cold Spring Harbor Laboratory Press,1989,Chapters 10和11,其所有公开内容都通过参考引用并入本文。
例如,核酸探针用下述物质标记,例如,放射性核素,例如3H,32P,33P,14C,或35S;重金属;能起到标记配体的特异性结合对成员功能的配体(例如,生物素,抗生物素蛋白或抗体);荧光分子;化学发光分子;酶等。
通过Rigby等人(1977),J.Mol.Biol.113:237-251的切口平移方法,或通过Fienberg等人(1983),Anal.Biochem.132:6-13的随机引物法,可以将探针标记成高比放射性,所述文献的所有公开内容都通过参考引用并入本文。后者是从单链DNA或从RNA模板合成高比放射性的32p-标记的探针的选择方法。例如,通过根据切口平移方法用高放射性的核苷酸替换现有的核苷酸,可以制备比放射性大大超过108cpm/微克的32P-标记的核酸探针。然后通过使杂交的滤膜曝光于照相胶片,可以进行杂交的放射自显影检测。对杂交的滤膜曝光的照相胶片的光密度扫描,会提供miR基因转录物水平的精确测量。使用另一个方案,通过计算机化成像系统,例如可从AmershamBiosciences,Piscataway,NJ得到的Molecular Dynamics 400-B 2D磷光计,可以定量miR基因转录物水平。
当DNA或RNA探针的放射性核素标记不可行时,随机-引物方法可以用于将类似物例如dTTP类似物5-(N-(N-生物素基-ε-氨基己酰基)-3-氨基烯丙基)脱氧尿苷三磷酸掺入探针分子中。通过与生物素-结合蛋白(例如抗生物素蛋白、链霉抗生物素和抗体(例如,抗-生物素抗体),其偶联到荧光染料或产生颜色反应的酶上)的反应,可以检测生物素化的探针寡核苷酸。
除了RNA印迹和其它RNA杂交技术以外,使用原位杂交技术,可以测定RNA转录物的水平。该技术需要比RNA印迹技术更少的细胞,包括将整个细胞放置在显微镜盖玻片上,用含有放射性的或其它标记的核酸(例如,cDNA或RNA)探针的溶液探测细胞的核酸内容物。该技术特别适用于分析来自受试者的组织活检样品。原位杂交技术的实践更详细地描述在美国专利号5,427,916,其全部公开内容通过参考引用并入本文。从表1a和表1b中提供的核酸序列,可以生成适用于给定miR基因产物的原位杂交的探针,包括、但不限于,与目标miR基因产物具有至少约70%、75%、80%、85%、90%、95%、98%、99%或完全互补性的探针,如上所述。
通过逆转录miR基因转录物,随后通过聚合酶链式反应(RT-PCR)扩增逆转录的转录物,也可以测定细胞中miR基因转录物的相对数目。可通过与内部标准例如来自存在于相同样品中的“管家”基因的mRNA的水平比较,来定量miR基因转录物的水平。用作内部标准的合适的“管家”基因包括例如肌球蛋白或甘油醛-3-磷酸脱氢酶(G3PDH)。用于定量和半-定量RT-PCR的方法和其变化形式,是本领域技术人员众所周知的。
在一些情况下,可能希望同时测定样品中许多不同miR基因产物的表达水平。在其它情况下,可能希望测定所有已知的与癌症相关的miR基因的转录物的表达水平。评估数百个miR基因或基因产物的癌症特异性表达水平是非常耗时的,并且需要大量总RNA(对于每个RNA印迹至少20μg)和需要放射性同位素的放射自显影技术。
为克服这些限制,可构建微芯片形式(即,微阵列)的寡物文库,其包含对于一组miR基因特异性的一组寡核苷酸(例如,寡脱氧核苷酸)探针。通过使用该微阵列,可通过逆转录RNA以产生一组靶寡脱氧核苷酸,然后使其与微阵列上的探针寡脱氧核苷酸杂交,从而产生杂交或表达谱,来测定生物样品中多种微小RNA的表达水平。然后科将测试样品的杂交谱与对照样品进行比较,以确定在实体癌细胞中具有改变的表达水平的微小RNA。如本文所用的,“探针寡核苷酸”或“探针寡脱氧核苷酸”是指能够与靶寡核苷酸杂交的寡核苷酸。“靶寡核苷酸”或“靶寡脱氧核苷酸”是指待检测(例如通过杂交)的分子。“miR-特异性的探针寡核苷酸”或“对miR特异性的探针寡核苷酸”是指具有经选择与特定miR基因产物杂交或与该特定miR基因产物的逆转录物杂交的序列的探针寡核苷酸。
特定样品的“表达谱”(expression profile)或“杂交谱”(hybridization profile)基本上是样品的状态的指纹图谱;尽管两种状态可具有相似表达的任何特定基因,但同时评估多个基因可允许产生对于细胞状态独特的基因表达谱。即,正常组织可与癌(例如肿瘤)组织区别,并且在癌组织内,可确定不同的预后状态(例如,良好的或较差的长期存活希望)。通过比较不同状态中的实体癌组织的表达谱,可获得关于哪些基因在这些状态每一种中是重要的(包括基因的增量调节和减量调节)信息。在实体癌组织中差异表达的序列的鉴定以及导致不同的预后结果的差异表达的鉴定,允许以许多方式使用该信息。例如,可评价特定的治疗方案(例如,以确定化疗药物是否起着改善特定患者的长期预后的作用)。类似地,可通过将患者的样品与已知的表达谱比较来进行或确认诊断。此外,这些基因表达谱(或个别基因)允许筛选抑制实体癌表达谱或将不良预后谱转变成更好的预后谱的药物候选品。
因此,本发明提供了诊断受试者是否患有实体癌或处于发生实体癌的风险中的方法,其包括从获自受试者的测试样品逆转录RNA,以提供一组靶寡脱氧核苷酸,使所述靶寡脱氧核苷酸与包含miRNA-特异性探针寡核苷酸的微阵列杂交,以提供测试样品的杂交谱,并对比测试样品杂交谱与从对照样品或参照标准产生的杂交谱,其中至少一种miRNA的信号的改变指示着受试者患有实体癌或处于发生实体癌的风险中。在一个实施方案中,所述微阵列包含针对所有已知人miRNA的实质部分的miRNA-特异性探针寡核苷酸。在一个特定的实施方案中,所述微阵列包含针对选自下述的一种或多种miRNA的miRNA-特异性探针寡核苷酸:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
可以从由已知的miRNA序列产生的基因特异性寡核苷酸探针制备微阵列。微阵列可包含对于每种miRNA的两种不同的寡核苷酸探针,一种包含活性的成熟序列,另一种对于该miRNA的前体是特异性的。微阵列还可以包含对照,例如一个或多个与人直系同源物相异仅少数碱基的小鼠序列,该序列可用作杂交严格性条件的对照。还可将来自两个物种的tRNA和其它RNA(例如,rRNA,mRNA)印在微芯片上,为特异性杂交提供内部的、相对稳定的阳性对照。还可在微芯片上包含非特异性杂交的一个或多个合适的对照。为此,基于与任何已知的miRNA不存在任何同源性来选择序列。
可使用本领域内已知的技术制造微阵列。例如,在位置C6上对合适长度例如40个核苷酸的探针寡核苷酸进行5’-胺修饰,然后使用可商购获得的微阵列系统例如GeneMachine OmniGridTM 100Microarrayer和Amersham CodeLinkTM活化载玻片进行印制。通过用标记的引物逆转录靶RNA来制备相应于靶RNA的标记的cDNA寡物。在第一链合成后,使RNA/DNA杂交体变性以降解RNA模板。然后将所制备的标记的靶cDNA在杂交条件下与微阵列芯片杂交,所述条件是例如在25℃下在6X SSPE/30%甲酰胺中进行18小时,然后在37℃下在0.75XTNT(Tris HC1/NaCl/吐温20)中洗涤40分钟。杂交在阵列上在固定的探针DNA识别样品中的互补靶cDNA的位置上发生。标记的靶cDNA标记了阵列上发生结合的确切位置,从而允许自动检测和定量。输出由一列杂交事件组成,其显示了特定cDNA序列的相对丰度,从而显示患者样品中相应的互补miR的相对丰度。根据一个实施方案,标记的cDNA寡物是从生物素标记的引物制备的生物素标记的cDNA。然后通过使用例如链霉抗生物素-Alexa647缀合物直接检测含生物素的转录物来处理微阵列和使用常规的扫描方法扫描微阵列。阵列上各点的图像强度与患者样品中相应的miR的丰度成比例。
阵列的使用对于miRNA表达检测具有几个有利方面。第一,可在一个时间点在相同的样品中鉴定数百个基因的整体表达。第二,通过对寡核苷酸探针的仔细设计,可鉴定成熟和前体分子的表达。第三,与RNA印迹分析相比,芯片需要少量的RNA,并且使用2.5μg的总RNA可提供可重复的结果。相对有限数量的miRNA(每个物种数百个)允许构建几个物种的共同微阵列,对于各物种具有不同的寡核苷酸探针。该工具允许对多种不同条件下各已知miR的跨物种表达进行分析。
除了用于特定miR的定量表达水平测定外,包含相应于相当大部分的miRNome(优选整个miRNome)的miRNA特异性探针寡核苷酸的微芯片可用于确定miR基因表达谱,从而进行miR表达模式的分析。不同的miR特征谱可与已建立的疾病标记或直接与疾病状态相关联。
根据本文描述的表达谱确定分析法,定量逆转录来自获自怀疑具有癌症(例如,实体癌)的受试者的样品的总RNA,以提供一组与样品中的RNA互补的标记的靶寡脱氧核苷酸。然后使所述靶寡脱氧核苷酸与包含miRNA特异性探针寡核苷酸的微阵列杂交,从而提供样品的杂交谱。结果是展示样品中miRNA的表达模式的样品的杂交谱。杂交谱包含来自样品的靶寡脱氧核苷酸与微阵列中的miRNA特异性探针寡核苷酸结合产生的信号。该谱可记录为结合的存在或不存在(信号相对于零信号)。更优选,记录的谱包括来自各杂交的信号的强度。将谱与从正常即非癌性的对照样品产生的杂交谱进行比较。信号的改变指示着受试者中存在癌症或发生癌症的倾向。
用于测量miR基因表达的其它技术也在本领域技术人员的技能范围之内,并且包括用于测量RNA转录和降解的速率的各种技术。
本发明也提供了确定患有实体癌的受试者的预后的方法,其包括测量来自受试者的测试样品中与实体癌的特定预后(例如,好的或积极的预后,差的或不良的预后)有关的至少一种miR基因产物的水平。根据这些方法,与对照样品中相应的miR基因产物的水平相比,测试样品中与特定预后有关的miR基因产物的水平的改变,指示着受试者患有具有特定预后的实体癌。在一个实施方案中,所述miR基因产物与不良(即,差)预后有关。不良预后的实例包括、但不限于,低生存率和快速疾病进展。在某些实施方案中,如下测量至少一种miR基因产物的水平:从获自受试者的测试样品逆转录RNA,以提供一组靶寡脱氧核苷酸,使所述靶寡脱氧核苷酸与包含miRNA-特异性探针寡核苷酸的微阵列杂交,以提供测试样品的杂交谱,并对比测试样品杂交谱与从对照样品产生的杂交谱。
不希望受任何一种理论的束缚,认为细胞中一种或多种miR基因产物的水平的变化可导致这些miR的一个或多个目标靶失调,这可导致实体癌的形成。因此,改变miR基因产物的水平(例如,通过减少在实体癌细胞中被增量调节的miR基因产物的水平,通过增加在实体癌细胞中被减量调节的miR基因产物的水平)可成功地治疗实体癌。
因此,本发明包括抑制患有或被怀疑患有实体癌的受试者的肿瘤发生的方法,其中在受试者的癌细胞中至少一种miR基因产物失调(例如,减量调节,增量调节)。当癌细胞中的至少一种分离的miR基因产物被减量调节(例如miR-145,miR-155,miR-218-2)时,该方法包括,施用有效量的所述至少一种分离的miR基因产物、或其分离的变体或生物活性片段,从而抑制受试者中癌细胞的增殖。在一个实施方案中,施用的分离的miR基因产物不是miR-15a或miR-16-1。在另一个实施方案中,所述miR基因产物不是miR159-1或miR-192。在另一个实施方案中,所述miR基因产物不是miR-186,miR-101-1,miR-194,miR-215,miR-106b,miR-25,miR-93,miR-29b,miR-29a,miR-96,miR-182s,miR-182as,miR-183,miR-129-1,let-7a-1,let-7d,let-7f-1,miR-23b,miR-24-1,miR-27b,miR-32,miR-159-1,miR-192,miR-125b-1,let-7a-2,miR-100,miR-196-2,miR-148b,miR-190,miR-21,miR-301,miR-142s,miR-142as,miR-105-1,或miR-175。在另一个实施方案中,所述miR基因产物不是miR-21,miR-301,miR-142as,miR-142s,miR-194,miR-215,或miR-32。在另一个实施方案中,所述miR基因产物不是miR-148,miR-10a,miR-196-1,miR-152,miR-196-2,miR-148b,miR-10b,miR-129-1,miR-153-2,miR-202,miR-139,let-7a,let-7f,或let-7d。在另一个实施方案中,所述miR基因产物不是miR-30,miR-15b,miR-16-2,miR-217,miR-205,miR-204,miR-103,miR-107,miR-9,和miR-137。在另一个实施方案中,所述miR基因产物不是miR-145,miR-21,miR-155,miR-10b,miR-125b-1,miR-125b-2,let7a-2,let7a-3,let-7d,miR-122a,miR-191,miR-206,miR-210,let-7i,miR-009-1(miR131-1),miR-34(miR-170),miR-102(miR-29b),miR-123(miR-126),miR-140-as,miR-125a,miR-194,miR-204,miR-213,let-7f-2,miR-101,miR-128b,miR-136,miR-143,miR-149,miR-191,miR-196-1,miR-196-2,miR-202,miR-103-1,或miR-30c。在另一个实施方案中,所述miR基因产物不是miR-21,miR-125b-1,let-7a-2,let-7i,miR-100,let-7g,miR-31,miR-32a-1,miR-33b,miR-34a-2,miR-101-1,miR-135-1,miR-142as,miR-142s,miR-144,miR-301,miR-29c,miR-30c,miR-106a,或miR-29b-1。
例如,当受试者癌细胞中的miR基因产物被减量调节时,给受试者施用有效量的分离的miR基因产物可以抑制癌细胞的增殖。施用给受试者的分离的miR基因产物可以与在癌细胞中减量调节的内源野生型miR基因产物(例如,表1a或表1b所示的miR基因产物)相同,或可以是其变体或生物活性片段。如本文所定义的,miR基因产物的"变体"是指与相应的野生型miR基因产物具有小于100%同一性、且具有相应的野生型miR基因产物的一种或多种生物活性的miRNA。这样的生物活性的实例包括、但不限于,抑制靶RNA分子的表达(例如,抑制靶RNA分子的翻译,调控靶RNA分子的稳定性,抑制靶RNA分子的加工)和抑制与实体癌有关的细胞过程(例如,细胞分化,细胞生长,细胞死亡)。这些变体包括物种变体和作为miR基因中的一个或多个突变(例如,置换,缺失,插入)的结果的变体。在某些实施方案中,所述变体与相应的野生型miR基因产物至少约70%、75%、80%、85%、90%、95%、98%或99%相同。
如本文所定义的,miR基因产物的"生物活性片段"是指具有相应的野生型miR基因产物的一种或多种生物活性的的miR基因产物的RNA片段。如上所述,这样的生物活性的实例包括、但不限于,抑制靶RNA分子的表达和抑制与实体癌有关的细胞过程。在某些实施方案中,所述生物活性片段的长度是至少约5,7,10,12,15,或17个核苷酸。在一个具体的实施方案中,可以与一种或多种其它的抗癌治疗相组合,将分离的miR基因产物施用给受试者。合适的抗癌治疗包括、但不限于,化疗,放疗和其组合(例如,放化疗)。
当至少一种分离的miR基因产物在癌细胞中增量调节时,该方法包括,给受试者施用有效量的至少一种抑制所述至少一种miR基因产物的表达的化合物(在本文中称作抑制miR基因表达的化合物),从而抑制实体癌细胞的增殖。在一个特定的实施方案中,所述至少一种抑制miR表达的化合物对选自下述的miR基因产物是特异性的:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。抑制miR基因表达的化合物可以与一种或多种其它抗癌治疗组合施用给受试者。合适的抗癌治疗包括、但不限于,化疗,放疗和其组合(例如,放化疗)。
如本文所用的,术语“治疗”、“医治”和“医疗”是指改善与疾病或病症例如实体癌相关的症状,包括阻止或延迟疾病症状的发作和/或减少疾病或病症的症状的严重度或频率。术语“受试者”、“患者”和“个体”在本文定义为包括动物例如哺乳动物,包括但不限于,灵长类动物、牛、绵羊、山羊、马、狗、猫、兔子、豚鼠、大鼠、小鼠或其它牛族动物、羊科动物、马科动物、犬科动物、猫科动物、啮齿类动物或鼠类物种。在优选实施方案中,动物是人。
如本文所用的,分离的miR基因产物的“有效量”是足以抑制罹患实体癌的受试者中癌细胞增殖的量。通过考虑诸如受试者的身材大小和体重、疾病侵入的程度、受试者的年龄、健康和性别、给药途径以及给药是局部的还是全身性的等因素,本领域技术人员可容易地确定对给定受试者施用的miR基因产物的有效量。
例如,分离的miR基因产物的有效量可基于被治疗的肿瘤块的近似重量。可通过计算团块的近似体积确定肿瘤块的近似重量,其中1立方厘米的体积大致相当于1克。基于肿瘤块的重量的分离的miR基因产物的有效量可以在约10-500微克/克的肿瘤块的范围内。在某些实施方案中,肿癌块可以是至少约10微克/克的肿瘤块,至少约60微克/克的肿瘤块或至少约100微克/克的肿瘤块。
分离的miR基因产物的有效量还可基于被治疗的受试者的近似或估计的体重。优选,如本文所描述的,通过胃肠外或肠内给药施用该有效量。例如,对受试者施用的分离的miR基因产物的有效量可在约5至3000微克/kg的体重,约700至1000微克/kg的体重的范围冉变动,或大于约1000微克/kg的体重。
本领域技术人员也可容易地确定对给定的受试者施用分离的miR基因产物的合适的给药方案。例如,可对受试者施用miR基因产物一次(例如,作为单次注射或沉积(deposition))。或者,可每天对受试者施用miR基因产物1次或2次,进行约3至约28天,更特别地约7至约10天的时期。在特定的给药方案中,每天1次施用miR基因产物,进行7天。当给药方案包括多次施用时,要理解对受试者施用的miR基因产物的有效量可包括在整个给药方案中施用的基因产物的总量。
如本文所用的,“分离的”miR基因产物是合成的或通过人干预从天然状态改变的或取出的产物。例如,合成的miR基因产物或部分地或完全地与其天然状态的共存材料分离的miR基因产物被认为是“分离的”。分离的miR基因产物可以基本上纯化的形式存在,或可存在于已递送了该miR基因产物的细胞中。因此,有意递送至细胞或有意在细胞中表达的miR基因产物被认为是“分离的”miR基因产物。在细胞内从miR前体分子产生的miR基因产物也被认为是“分离的”分子。根据本发明,本文所述的分离的miR基因产物可以用于生产治疗受试者(例如,人)的实体癌的药物。
可使用许多标准技术获得分离的miR基因产物。例如,可使用本领域内已知的方法化学合成或重组产生miR基因产物。在一个实施方案中,使用适当保护的核糖核苷亚磷酰胺和常规的DNA/RNA合成仪,化学合成miR基因产物。合成的RNA分子或合成试剂的商业提供商包括例如Proligo(Hamburg,Germany)、Dharmacon Research(Lafayette,CO,U.S.A.)、Pierce Chemical(part of Perbio Science,Rockford,IL,U.S.A.)、Glen Research(Sterling,VA,U.S.A.)、ChemGenes(Ashland,MA,U.S.A.)和Cruachem(Glasgow,UK)。
或者,可使用任何合适的启动子从重组环状或线性DNA质粒表达miR基因产物。用于从质粒表达RNA的合适的启动子包括例如U6或H1RNA pol III启动子序列或巨细胞病毒启动子。其它合适的启动子的选择在本领域技术人员的技能范围之内。本发明的重组质粒还可包含用于在癌细胞中表达miR基因产物的诱导型或调控型启动子。
可通过标准技术从培养细胞表达系统分离从重组质粒表达的miR基因产物。也可将从重组质粒表达的miR基因产物递送至和直接在癌细胞中表达。下面更详细地讨论重组质粒用于将miR基因产物递送至癌细胞的用途。
可从分开的重组质粒表达miR基因产物,或可从相同的重组质粒表达它们。在一个实施方案中,miR基因产物从单个质粒表达为RNA前体分子,然后前体分子通过合适的加工系统(包括但不限于存在于癌细胞内的加工系统)加工成功能性miR基因产物。其它合适的加工系统包括,例如,体外果蝇细胞裂解物系统(lysate system)(例如,如属于Tuschl等人的美国公开专利申请号2002/0086356中描述的,其全部公开内容通过参考引用并入本文)和大肠杆菌RNA酶III系统(例如,如属于Yang等人的美国公开专利申请号2004/0014113中描述的,其全部公开内容通过参考引用并入本文)。
适合用于表达miR基因产物的质粒的选择,用于将核酸序列插入质粒以表达基因产物的方法和将重组质粒递送入目的细胞的方法在本领域技术人员的技能范围之内。参见,例如,Zeng等人(2002),Molecular Cell 9:1327-1333;Tuschl(2002),Nat.Biotechnol,20:446-448;Brummelkamp等人(2002),Science 296:550-553;Miyagishi等人(2002),Nat.Biotechnol.20:497-500;Paddison等人(2002),GenesDev.16:948-958;Lee等人(2002),Nat.Biotechnol.20:500-505;和Paul等人(2002),Nat.Biotechnol.20:505-508,其全部公开内容通过参考引用并入本文。
在一个实施方案中,表达miR基因产物的质粒包含在CMV即早期启动子控制之下的编码miR前体RNA的序列。如本文所用的,“在启动子控制之下”意指编码miR基因产物的核酸序列位于启动子的3’,这样启动子可起始编码miR基因产物的序列的转录。
也可从重组病毒载体表达miR基因产物。可从两个分开的重组病毒载体或从相同的病毒载体表达miR基因产物。可通过标准技术从培养细胞表达系统分离从重组病毒载体表达的RNA,或可在癌细胞中直接表达它。下面更详细地描述重组病毒载体将miR基因产物递送至癌细胞的用途。
本发明的重组病毒载体包含编码miR基因产物的序列和用于表达RNA序列的任何合适的启动子。合适的启动子包括、但不限于例如U6或H1 RNA pol III启动子序列或巨细胞病毒启动子。其它合适的启动子的选择在本领域技术人员的技能范围之内。本发明的重组病毒载体还可包含用于在癌细胞中表达miR基因产物的诱导型或调控型启动子。
可使用能够接受miR基因产物的编码序列的任何病毒载体;例如来源于腺病毒(AV)、腺伴随病毒(AAV)、逆转录病毒(例如,慢病毒(LV)、杆状病毒、鼠白血病病毒)、疱疹病毒等的载体。适当时,可通过用包膜蛋白和来自其它病毒的其它表面蛋白假型化载体或通过置换不同的病毒衣壳蛋白来改变病毒载体的向性。
例如,可用来自水泡性口膜炎病毒(VSV)、狂犬病毒病毒、埃博拉病毒、莫科拉病等的表面蛋白假型化本发明的慢病毒载体。通过对载体进行基因工程改造以表达不同的衣壳蛋白血清型来产生本发明的AAV载体,从而使其靶向不同的细胞。例如,在血清2型基因组上表达血清2型衣壳的AAV载体称为AAV2/2。可用血清5型衣壳蛋白基因取代AAV2/2载体中的该血清2型衣壳蛋白基因以产生AAV2/5载体。用于构建表达不同的衣壳蛋白血清型的AAV载体的技术在本领域技术人员的技能范围之内;参见,例如,Rabinowitz,J.E.,等人(2002),J.Virol.76:791-801,其全部公开内容通过参考引用并入本文。
适合用于本发明的重组病毒载体的选择、用于将表达RNA的核酸序列插入载体的方法、将病毒载体递送至目的细胞的方法以及表达的RNA产物的回收在本领域技术人员的技能范围之内。参见,例如,Dornburg(1995),Gene Therap.2:301-310;Eglitis(1988),Biotechniques 6:608-614;Miller(1990),Hum.Gene Therap.1:5-14;和Anderson(1998),Nature 392:25-30,其全部公开内容通过参考引用并入本文。
特别合适的病毒载体是来源于AV和AAV的载体。用于表达本发明的miR基因产物的合适的AV载体、用于构建重组AV载体的方法以及将载体递送入靶细胞的方法描述于Xia等人(2002),Nat.Biotech.20:1006-1010中,其全部公开内容通过参考引用并入本文。用于表达miR基因产物的合适的AAV载体、用于构建重组AAV载体的方法以及将载体递送入靶细胞的方法描述于Samulski等人(1987),J.Virol.61:3096-3101;Fisher等人(1996),J.Virol.,70:520-532;Samulski等人(1989),J.Virol.63:3822-3826;美国专利号5,252,479;美国专利号5,139,941;国际专利申请号WO 94/13788;和国际专利申请号WO 93/24641,其全部公开内容通过参考引用并入本文。在一个实施方案中,从包含CMV立即早期启动子的单个重组AAV载体表达miR基因产物。
在某一实施方案中,本发明的重组AAV病毒载体包含在人U6 RNA的控制下、与polyT终止序列可操作连接的编码miR前体RNA的核酸序列。如本文所用的,“与polyT终止序列可操作连接”是指编码有义或反义链的核酸序列以5’方向与polyT终止信号直接相邻。在从载体转录miR序列的过程中,polyT终止信号起着终止转录的作用。
在本发明的治疗方法的其它实施方案中,可对受试者施用有效量的至少一种抑制miR表达的化合物。如本文所用的,“抑制miR表达”是指在治疗后miR基因产物的前体和/或活性、成熟形式的产量比治疗前产生的量低。通过使用例如上文关于诊断方法讨论的测定miR转录物水平的技术,本领域技术人员可容易地确定miR表达在癌细胞中是否已被抑制。抑制可在基因表达的水平上发生(即,通过抑制编码miR基因产物的miR基因的转录)或在加工水平上发生(例如,通过抑制miR前体加工成成熟的、活性miR)。
如本文所用的,抑制miR表达的化合物的“有效量”是足以在罹患癌症(例如,实体癌)的受试者中抑制癌细胞的增殖的量。通过考虑诸如受试者的身材大小和体重、疾病侵入的程度、受试者的年龄、健康和性别、给药途径和给药是局部的还是全身性的等因素,本领域技术人员可容易地确定抑制miR表达的化合物的有效量。
例如,抑制表达的化合物的有效量可基于待治疗的肿瘤块的近似重量,如本文所述。抑制miR表达的化合物的有效量也可基于待治疗的受试者的近似或估计重量,如本文所述。
本领域技术人员也可容易地确定对给定的受试者施用抑制miR表达的化合物的合适的给药方案。
用于抑制miR基因表达的合适的化合物包括双链RNA(例如短的或小的干扰RNA或“siRNA”)、反义核酸和酶RNA分子例如核酶。此类化合物中的各化合物可靶向给定的miR基因产物和干扰靶miR基因产物的表达(例如,通过抑制翻译,通过诱导切割和/或降解)。
例如,通过用与miR基因产物的至少一部分具有至少90%、例如至少95%、至少98%、至少99%、或100%序列同源性的分离的双链RNA("dsRNA")分子诱导对miR基因的RNA干扰,可以抑制给定miR基因的表达。在一个具体的实施方案中,dsRNA分子是"短的或小的干扰RNA"或"siRNA"。
用于本方法的siRNA包含长度为约17个核苷酸至约29个核苷酸,优选长度为约19至约25个核苷酸的短的双链RNA。siRNA包含根据标准的Watson-Crick碱基配对相互作用(以下称“碱基配对”)退火在一起的有义RNA链和互补反义RNA链。有义链包含基本上与靶miR基因产物内包含的核酸序列一致的核酸序列。
如本文所用的,siRNA中与靶mRNA中包含的靶序列“基本上一致”的核酸序列是与靶序列一致或与靶序列相异1个或2个核苷酸的核酸序列。siRNA的有义和反义链可包含两个互补的单链RNA分子,或可包含其中两个互补部分是碱基配对的并且通过单链“发夹”区域共价连接的单链分子。
siRNA可以是与天然存在的RNA不同在于一个或多个核苷酸的添加、缺失、置换和/或改变的改变的RNA。此类改变可包括非核苷酸材料的添加,例如添加至siRNA的末端或添加至siRNA的一个或多个内部核苷酸,或使siRNA对核酸酶降解具有抗性的修饰或用脱氧核糖核苷酸对siRNA中的一个或多个核苷酸的置换。
siRNA的一条或两条链还可包含3′突出端。如本文所用的,“3′突出端”是指从双链RNA链的3′末端延伸的至少一个未配对的核苷酸。因此,在某些实施方案中,siRNA包含长度为1个至约6个核苷酸(其包括核糖核苷酸或脱氧核糖核苷酸)、长度为1至约5个核苷酸、长度为1至约4个核苷酸或长度为约2至约4个核苷酸的至少一个3′突出端。在一个具体的实施方案中,3′突出端存在于siRNA的两条链上,且长度为2个核苷酸。例如,siRNA的各链包含二胸腺嘧啶脱氧核苷酸(dithymidylic acid)(“TT”)或二尿苷酸(“uu”)的3′突出端。
siRNA可通过化学或生物学的方法产生,或如上面关于分离的miR基因产物所描述的,可从重组质粒或病毒载体表达。用于产生和检测dsRNA或siRNA分子的示例性方法描述于属于Gewirtz的美国公开专利申请号2002/0173478和属于Reich等人的美国公开专利申请号2004/0018176,其全部公开内容通过参考引用并入本文。
还可通过反义核酸来抑制给定的miR基因的表达。如本文所用的,“反义核酸”是指通过RNA-RNA或RNA-DNA或RNA-肽核酸相互作用结合至靶RNA的核酸分子,其可改变靶RNA的活性。适合用于本发明的方法的反义核酸是通常包含与miR基因产物中的连续核酸序列互补的核酸序列的单链核酸(例如,RNA、DNA、RNA-DNA嵌合体、肽核酸(PNA))。反义核酸可包含与miR基因产物中的连续核酸序列50-100%互补、75-100%互补或95-100%互补的核酸序列。表1a和1b中提供了miR基因产物的核酸序列。不希望受限于任何理论,认为反义核酸激活RNA酶H或消化miR基因产物/反义核酸双链体的另一种细胞核酸酶。
反义核酸还可包含对核酸主链的修饰或对糖和碱基部分(或其等同物)的修饰,以增强靶特异性、对核酸酶的抗性、与分子的功效相关的递送或其它性质。此类修饰包括胆固醇部分、双链体插入剂(例如吖啶)或一种或多种抗核酸酶基团。
反义核酸可通过化学或生物学方法产生,或如上面关于分离的miR基因产物所描述的,可从重组质粒或病毒载体表达。用于产生和检测的示例性方法在本领域技术人员的技能范围之内;参见,例如,Stein和Cheng(1993),Science 261:1004和Woolf等人的美国专利号5,849,902,其全部公开内容通过参考引用并入本文。
还可用酶核酸抑制给定的miR基因的表达。如本文所用的,“酶核酸”是指包含具有与miR基因产物的连续核酸序列的互补性的底物结合区的核酸,其能够特异性切割miR基因产物。酶核酸底物结合区可以与miR基因产物中的连续核酸序列例如50-100%互补、75-100%互补或95-100%互补。酶核酸还可包含在碱基、糖和/或磷酸基团上的修饰。用于本发明的方法的示例性酶核酸是核酶。
酶核酸可通过化学或生物学方法产生,或如上面关于分离的miR基因产物所描述的,可从重组质粒或病毒载体表达。用于产生和检测dsRNA或siRNA分子的示例性方法描述于Werner和Uhlenbeck(1995),Nucleic Acids Res.23:2092-96;Hammann等人(1999),Antisense and Nucleic Acid Drug Dev.9:25-31;和属于Cech等人的美国专利号4,987,071,其全部公开内容通过参考引用并入本文。
至少一种miR基因产物或至少一种抑制miR表达的化合物的施用,将抑制患有实体癌的受试者中的癌细胞的增殖。如本文所用的,“抑制癌细胞的增殖”是指杀死细胞或永久性地或临时性地阻止或减缓细胞的生长。如果在施用miR基因产物或抑制miR基因表达的化合物后,受试者中癌细胞的数目保持恒定或减少,那么可推断此类细胞的增殖被抑制。如果癌细胞的绝对数目增加但肿瘤生长速率减小也可推断癌细胞的增殖被抑制。
可通过直接测量或通过从原发性或转移肿瘤块的大小估计来确定受试者体内的癌细胞的数目。例如,可通过免疫组织学方法、流式细胞计量术或设计用于检测癌细胞的特征性表面标记的其它技术测量受试者中的癌细胞数目。
可通过直接目视观察或通过诊断性影像学方法例如X射线、磁共振显像、超声和闪烁照相术确定肿瘤块的大小。如本领域内已知的,可在存在或不存在造影剂的情况下使用用于确定肿瘤块的大小的诊断性影像法。还可使用物理方法例如组织块的触诊或使用测量仪器例如测径器测量组织块来确定肿瘤块的大小。
可通过适合将这些化合物递送至受试者的癌细胞的任何方法对受试者施用miR基因产物或抑制miR基因表达的化合物。例如,可通过适合于用这些化合物或用包含编码这些化合物的序列的核酸转染受试者的细胞的方法来施用miR基因产物或抑制miR表达的化合物。在一个实施方案中,用包含编码至少一种miR基因产物或抑制miR基因表达的化合物的序列的质粒或病毒载体转染细胞。
用于真核细胞的转染方法在本领域内熟知,包括例如核酸至细胞的细胞核或前核的直接注射、电穿孔、脂质体转移或通过亲脂材料介导的转移、受体介导的核酸递送、bioballistic或粒子加速;磷酸钙沉淀和通过病毒载体介导的转染。
例如,可用脂质体转移化合物DOTAP(甲基硫酸N-[1-(2,3-二油酰氧)丙基]-N,N,N-三甲基-铵,Boehringer-Mannheim)或等同物例如LIPOFECTIN转染细胞。使用的核酸的量对于本发明的实践不是至关重要的;可用0.1-100微克的核酸/105个细胞获得可接受的结果。例如,可使用每105个细胞约0.5微克质粒于3微克DOTAP中的比率。
还可通过任何合适的肠内或胃肠外给药途径对受试者施用miR基因产物或抑制miR基因表达的化合物。用于本方法的合适的肠内给药途径包括例如口服、直肠或鼻内递送。合适的胃肠外给药途径包括例如血管内给药(例如,至脉管系统的静脉内快速注射、静脉输注、动脉内快速浓注、动脉内输注和导管滴注);组织外周和组织内注射(例如,瘤周和瘤内注射、视网膜内注射或视网膜下注射);皮下注射或沉积,包括皮下输注(例如通过渗透泵);对目的组织的直接施用,例如通过导管或其它安置装置(例如,视网膜弹丸剂或栓剂或包含多孔、无孔或凝胶状材料的植入体);以及吸入。特别适合的给药途径是注射、输注和直接至肿瘤的注射。
在本方法中,可将miR基因产物或抑制miR基因产物的表达的化合物作为裸RNA与递送试剂一起或作为核酸(例如,重组质粒或病毒载体)给受试者施用,所述核酸包含表达miR基因产物或抑制miR基因表达的化合物的序列。合适的递送试剂包括例如Mirus Transit TKO亲脂试剂、lipofectin、lipofectamine、cellfectin、聚阳离子(例如,多聚赖氨酸)和脂质体。
包含表达miR基因产物或抑制miR基因表达的化合物的序列的重组质粒和病毒载体以及用于递送此类质粒和载体至癌细胞的技术在本文讨论,和/或是本领域众所周知的。
在一个具体的实施方案中,脂质体用于将miR基因产物或抑制miR基因表达的化合物(或包含编码它们的序列的核酸)递送至受试者。脂质体也可以增加基因产物或核酸的血液半衰期。可从标准的形成小囊泡的脂质(其通常包括中性或带负电荷的磷脂和固醇例如胆固醇)形成用于本发明的合适的脂质体。通常通过考虑诸如想要的脂质体大小和血流中脂质体的半衰期等因素,指导脂质的选择。用于制备脂质体的许多方法是已知的,例如,如在Szoka等人(1980),Ann.Rev.Biophys.Bioeng.9:467;和美国专利号4,235,871、4,501,728、4,837,028和5,019,369(其全部公开内容通过参考引用并入本文)中描述。
用于本方法的脂质体可包含将脂质体靶向癌细胞的配体分子。结合癌细胞中普遍存在的受体的配体例如结合肿瘤细胞抗原的单克隆抗体是优选的。
还可对用于本方法的脂质体进行修饰,以避免被单核巨噬细胞系统(“MMS”)和网状内皮系统(“RES”)清除。此类经修饰的脂质体具有存在于表面上或整合入脂质体结构中的调理作用抑制部分。在特别优选实施方案中,本发明的脂质体可包含调理作用抑制部分和配体两者。
用于制备本发明的脂质体的调理作用抑制部分通常是结合至脂质体膜的大的亲水聚合物。如本文所用的,当其例如通过脂溶性锚嵌入膜本身中或通过与膜脂质的活性基团直接结合而被化学地或物理地附着至膜时,调理作用抑制部分“结合”至脂质体膜。这些调理作用抑制性亲水聚合物形成了显著减少脂质体被MMS和RES摄取的保护表面层;例如,如美国专利号4,920,016中所描述的,其全部公开内容通过参考引用并入本文。
适合用于修饰脂质体的调理作用抑制部分优选是具有约500至约40,000道尔顿和优选约2,000至约20,000道尔顿的数量平均分子量的水溶性聚合物。此类聚合物包括聚乙二醇(PEG)或聚丙二醇(PPG)衍生物;例如甲氧基PEG或PPG,和PEG或PPG硬脂酸酯;合成聚合物,例如聚丙烯酰胺或聚N-乙烯基吡咯酮;线性的、分支的或树状聚酰胺-胺(polyamidoamines);聚丙烯酸;多元醇,例如羧基或氨基化学连接至其的聚乙烯醇和聚木糖醇,以及神经节苷脂例如神经节苷脂GM1。PEG、甲氧基PEG或甲氧基PPG或其衍生物的共聚物也是合适的。此外,调理作用抑制性聚合物可以是PEG与多聚氨基酸、多糖、聚酰胺-胺、聚乙烯胺或多核苷酸的嵌段共聚物。调理作用抑制性聚合物也可以是包含氨基酸或羧酸例如半乳糖醛酸、葡糖醛酸、甘露糖醛酸、透明质酸、果胶酸、神经氨酸、海藻酸、角叉菜胶的天然多糖;氨化多糖或寡糖(线性或分支的);或羧化多糖或低聚糖,例如与碳酸的衍生物反应,获得羧基的连接。优选,调理作用抑制部分是PEG、PPG或其衍生物。用PEG或PEG衍生物修饰的脂质体有时称为“PEG化脂质体”。
可通过许多熟知的技术中的任一种将调理作用抑制部分与脂质体膜结合。例如,可将PEG的N-羟基琥珀酰亚胺酯结合至磷脂酰乙醇胺脂溶性锚,然后再将其结合至膜。类似地,可使用Na(CN)BH3和溶剂混合物(例如以30∶12比例的四氢呋喃和水)在60℃下通过还原氨化作用用硬脂酰胺脂溶性锚衍生葡聚糖聚合物。
用调理作用抑制部分修饰的脂质体在循环中比未修饰的脂质体保持长得多的时间。因此,这样的脂质体有时称为“秘密(stealth)”脂质体。已知秘密脂质体在由多孔的或“渗漏的”微血管滋养的组织中积累。因此,特征在于该微血管缺陷的组织例如实体瘤将有效率地积累这些脂质体;参见Gabizon,等人(1988),Proc.Natl.Acad.Sci.,U.S.A.,18:6949-53。此外,减少的由RES进行的吸收通过防止脂质体在肝和脾中大量积累而降低了秘密脂质体的毒性。因此,用调理作用抑制部分修饰的脂质体特别适合将miR基因产物或抑制miR基因表达的化合物(或包含编码它们的序列的核酸)递送至肿瘤细胞。
按照本领域内已知的技术,在给受试者施用之前,可将miR基因产物或抑制miR基因表达的化合物配制为药物组合物,有时称为“药物”。因此,本发明包括用于治疗实体癌的药物组合物。在一个实施方案中,药物组合物包含至少一种分离的miR基因产物、或其分离的变体或生物活性片段,和药学上可接受的载体。在一个具体实施方案中,所述至少一种miR基因产物对应于这样的miR基因产物,即相对于合适的对照细胞,该miR基因产物在实体癌细胞中具有降低的表达水平。在某些实施方案中,所述分离的miR基因产物选自:miR-145,miR-155,miR-218-2其组合。
在其它实施方案中,本发明的药物组合物包含至少一种抑制miR表达的化合物。在一个特定的实施方案中,所述至少一种抑制miR表达的化合物对在实体癌细胞中的表达大于对照细胞的miR基因是特异性的。在某些实施方案中,所述抑制miR表达的化合物对一种或多种选自下述的miR基因产物是特异性的:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
本发明的药物组合物的特征在于是至少无菌的和无热原的。如本文所用的,“药物组合物”包括用于人和兽医用途的制剂。用于制备本发明的药物组合物的方法在本领域技术人员的技能范围之内,例如,如Remington′s Pharmaceutical Science,第17版,Mack PublishingCompany,Easton,Pa.(1985)中所描述的,其全部公开内容通过参考引用并入本文。
本发明的药物组合物包含与药学上可接受的载体相混合的至少一种miR基因产物或抑制miR基因表达的化合物(或至少一种包含编码它们的序列的核酸)(例如,0.1-90%重量)或其生理上可接受的盐。在某些实施方案中,本发明的药物组合物另外包含一种或多种抗癌剂(例如,化疗剂)。本发明的药物制剂也可以包含由脂质体包封的至少一种miR基因产物或抑制miR基因表达的化合物(或至少一种包含编码它们的序列的核酸),和药学上可接受的载体。在一个实施方案中,药物组合物包含不是miR-15和/或miR-16的miR基因或基因产物。
特别合适的药学上可接受的载体是水、缓冲水溶液、生理盐水、0.4%的盐水、0.3%甘氨酸、透明质酸等。
在一个具体实施方案中,本发明的药物组合物包含对核酸酶的降解具有抗性的至少一种miR基因产物或抑制miR基因表达的化合物(或至少一种包含编码它们的序列的核酸)。本领域技术人员可容易地合成对核酸酶具有抗性的核酸,例如通过将一个或多个在2’位置被修饰的核糖核苷酸掺入miR基因产物。合适的2’-修饰的核糖核苷酸包括在2’位置用氟、氨基、烷基、烷氧基和O-烯丙基修饰的核糖核苷酸。本发明的药物组合物还可包含常规药物赋形剂和/或添加剂。合适的药物赋形剂包括稳定剂、抗氧化剂、渗透压调节剂(osmolalityadjusting agent)、缓冲剂和pH调节剂。合适的添加剂包括例如生理生物相容性缓冲剂(例如,盐酸氨丁三醇(tromethaminehydrochloride))、螯合剂(例如,DTPA或DTPA-双酰胺)或钙螯合物(例如,DTPA钙、CaNaDTPA-双酰胺)的加入,或任意地,钙或钠盐(例如,氯化钙、抗坏血酸钙、葡萄糖酸钙或乳酸钙)的加入。可包装本发明的药物组合物以使以液体形式使用或可将其冻干。
对于本发明的固体药物组合物,可使用常规的无毒性固体药学上可接受的载体例如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石粉、纤维素、葡萄糖、蔗糖、碳酸镁等。
例如,用于口服给药的固体药物组合物可包含上列的任何载体和赋形剂和10-95%,优选25%-75%的至少一种miR基因产物或抑制miR基因表达的化合物(或至少一种包含编码它们的序列的核酸)。用于气雾剂(吸入)给药的药物组合物可包含封装在上述脂质体中的按重量计算0.01-20%、优选按重量计算1%-10%的至少一种miR基因产物或抑制miR基因表达的化合物(或至少一种包含编码它们的序列的核酸)和喷射剂。当需要时也可包含载体;例如用于鼻内递送的卵磷脂。
本发明的药物组合物可以进一步包含一种或多种抗癌剂。在一个具体的实施方案中,组合物包含至少一种miR基因产物或抑制miR基因表达的化合物(或至少一种包含编码它们的序列的核酸)和至少一种化疗剂。适用于本发明的方法的化疗剂,包括、但不限于,DNA-烷化剂,抗肿瘤抗生素剂,抗代谢剂,微管蛋白稳定剂,微管蛋白去稳定剂,激素拮抗剂,拓扑异构酶抑制剂,蛋白激酶抑制剂,HMG-CoA抑制剂,CDK抑制剂,细胞周期蛋白抑制剂,胱天蛋白酶抑制剂,金属蛋白酶抑制剂,反义核酸,三链螺旋DNA,核酸适体,和分子修饰的病毒、细菌和外毒素试剂。适用于本发明的组合物的试剂的实例包括、但不限于,阿糖胞苷,甲氨蝶呤,长春新碱,依托泊苷(VP-16),多柔比星(阿霉素),顺铂(CDDP),地塞米松,arglabin,环磷酰胺,沙可来新,甲基亚硝基脲,氟尿嘧啶,5-氟尿嘧啶(5FU),长春碱,喜树碱,放线菌素-D,丝裂霉素C,过氧化氢,奥沙利铂,伊立替康,托泊替康,亚叶酸,卡莫司汀,链佐星,CPT-11,泰素,他莫昔芬,达卡巴嗪,利妥昔单抗,柔红霉素,1-β-D-阿糖呋喃胞嘧啶,伊马替尼,氟达拉滨,多西他赛和FOLFOX4。
本发明也包括鉴定肿瘤发生抑制剂的方法,其包括给细胞提供测试试剂,和测量细胞中至少一种miR基因产物的水平。在一个实施方案中,该方法包括,给细胞提供测试试剂,和测量与癌细胞中降低的表达水平有关的至少一种miR基因产物的水平。相对于合适的对照细胞(例如,没有提供试剂),在提供试剂后细胞中所述miR基因产物的水平的增加指示着测试试剂是肿瘤发生抑制剂。在一个特定的实施方案中,与癌细胞中降低的表达水平有关的至少一种miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
在其它实施方案中,该方法包括,给细胞提供测试试剂,和测量与癌细胞中增加的表达水平有关的至少一种miR基因产物的水平。相对于合适的对照细胞(例如,没有提供试剂),在提供试剂后细胞中所述miR基因产物的水平的降低指示着测试试剂是肿瘤发生抑制剂。在一个特定的实施方案中,与癌细胞中增加的表达水平有关的至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a。
合适的试剂包括但不限于药物(例如,小分子、肽),和生物大分子(例如,蛋白质、核酸)。可通过重组、合成方法产生该试剂,或其可从天然来源分离(即,纯化)。用于对细胞提供此类试剂的各种方法(例如,转染)在本领域内是熟知的,上文中描述了几种这样的方法。用于检测至少一种miR基因产物的表达的方法(例如,RNA印迹法、原位杂交法、RT-PCR、表达谱分析)在本领域内也是熟知的。上文中也描述了这些方法中的几种方法。
现在通过下列非限制性实施例解释本发明。
实施例
在实施例中使用下述的材料和方法:
样品
在该研究中使用了共540个样品,包括363个原发肿瘤样品和177个正常组织(表2)。下述的实体癌为例:肺癌,乳腺癌,前列腺癌,胃癌,结肠癌和胰腺内分泌肿瘤。所有样品在征得每位患者知情同意后获得,并在组织学上证实。将正常样品与来自患肺癌和胃癌的个体的样品配对,其它组织来自正常个体。通过合并5个不相关的正常组织,得到所有正常乳腺样品。根据生产商的说明书,使用TRIzolTM试剂(Invitrogen),从组织分离总RNA。
微小RNA微阵列
如前所述进行微阵列分析(Liu,C.-G.,等人,Proc.Natl.Acad.Sci.USA 101:11755-11760(2004))。简而言之,将5μg总RNA用于在miRNA微阵列芯片上的杂交。这些芯片含有基因-特异性的40-聚体寡核苷酸探针,它们通过接触技术来点印,并共价结合到聚合基质上。微阵列在25℃在6×SSPE(0.9M NaCl/60mM NaH2PO4·H2O/8mM EDTA,pH 7.4)/30%甲酰胺中杂交18小时,在37°C在0.75×TNT(Tris·HCl/NaCl/吐温20)中洗涤40min,通过链霉抗生物素-Alexa647(Molecular Probes)缀合物,使用生物素-标记的转录物的直接检测进行处理。使用微阵列扫描仪(GenePix Pro,Axon)扫描处理过的载玻片,激光设定在635nm,在固定的PMT设置,扫描分辨率是10mm。如所述(Calin,G.A.,等人,Proc.Natl.Acad.Sci.USA101:11755-11760(2004);Iorio,M.V.,等人,Cancer Res.65:7065-7070(2005))通过RNA印迹来证实数据。
表2.在研究中使用的样品(肿瘤和相应的正常样品)。
肿瘤类型 癌症样品 正常样品
肺癌 123 123
乳腺癌 79 6*
结肠癌 46 8
胃癌 20 21
内分泌胰腺肿瘤 39 12
前列腺癌 56 7
所有组织(527) 363 177
*每个样品5个不相关的正常乳腺组织的集合(总共30个不相关的个体)。
计算分析.
使用GenePix Pro(Axon)分析微阵列图像。对每个miRNA的重复点的平均值减去背景,标准化,并进行进一步分析。使用中位值阵列作为参照,通过使用每个芯片中位值标准化方法进行标准化。最后,选择测量在数据集合的2个类别中的至少最小类别中存在的miRNA。在统计分析之前,将呼叫缺失(Absent call)的阈值设定为4.5。该水平是在实验中检测到的平均最小强度水平。微小RNA命名是根据Genome Browser(www.genome.ucsc.edu)和在Sanger Center的微小RNA数据库(Griffiths-Jones,S.,Nuc leicAcids Res 32:D109-11(2004));在不符合的情况下,我们按照微小RNA数据库。在微阵列的显著性分析(SAM)内,使用t检验方法,鉴定差异表达的微小RNA(Tusher,V.G.,等人,Proc Natl Acad Sci USA 98:5116-21(2001)。在相对于所有测量的标准偏差的表达变化的基础上,SAM计算每个基因的评分。在SAM内,使用t检验。使用最近萎缩图心方法,确定微小RNA特征(signature)。该方法鉴定出将每种实体癌与它各自的正常对应物最佳表征区分开的基因亚群。借助于10-倍交叉验证,计算预测误差,对于每种癌症,我们得到产生最小预测误差的miR特征。通过随机置换分析进行再取样检验,以计算共有特征的p-值。
实施例1:人实体癌中微小RNA表达特征的鉴定
统计学
使用减少数目的肺样品(80个癌症和40个正常样品),进行组合的癌症/正常组织对比,以便在数字上平衡不同的组织,产生共404个样品。对于统计分析,从测量的228个miR中保留137个miR,它们的表达值在至少50%的样品中超过256(阈值)。T检验用于鉴定差异表达的微小RNA(表3)。为多个检验程序校正T检验的p-值,以控制I型误差率。通过用500,000个置换进行再取样,得到经调节后的p值(Jung,S.H.,等人Biostatistics 6:157-69(2005))。使用与Lu等人(Lu,J.,等人,Nature 435:834-8(2005))相同的方法,进行该分析,以便评价结果。
作为T检验的一个替代方案,使用微阵列的显著性分析(SAM)来鉴定差异表达的微小RNA。该方法允许控制假检出率(FDR)。选择δ,以产生小于或等于0.01的FDR。然后使用如在PAM(微阵列的预测分析)中实施的最近萎缩图心方法,鉴定出产生最佳肿瘤分类的微小RNA子集(即,它们最佳地预测这2个类别(癌症和正常))。借助于10-倍交叉验证的平均值,计算预测误差。选择在交叉验证后产生最小错分类误差的微小RNA。
结果
通过T-检验,得到43种差异表达的miR,经调节后的p-值低于0.05(表3)。当6种实体癌(乳腺,结肠,肺,胰腺,前列腺,胃)分组在一起时,与相应的正常组织相比,26种miR过表达,17种表达不足。这些结果表明,在实体癌中表达的miRNA的谱非常不同于正常细胞(43/137的miRNA,31%)。使用SAM,将49种miRNA鉴定为差异表达的,其中34种是增量调节的(表4)。使用PAM,将36种在癌症中过表达的miRNA(由正癌症评分指示)和21种减量调节的miR(由负癌症评分指示)鉴定为差异表达的(表5)。但是,这些分析不适于鉴定始终一致地导致转化的miR表达改变,因为miR表达是高度组织特异性的(He,L.,等人Nature 435:828-833(2005);也参见图1和图2)。
在图1中显示了使用228个miR,基于源自363个实体癌和177个正常样品的表达谱的miR聚类。使用在至少50%的研究用样品中表达的137个不同miRNA,构建出显示不同组织之间非常好的区分的树。
表3.相对于正常组织在6种实体癌类型中差异调节的miR(T检验统计学)*.
*-43种miR具有低于0.05的调节后p-值。在乳腺癌、结肠癌、肺癌、胰腺癌、前列腺癌、胃癌中,26种miR过表达,17种减量调节。
表4.相对于正常组织在6种实体癌类型中差异调节的miR(SAM,微阵列的显著性分析)*。
*-在乳腺癌、结肠癌、肺癌、胰腺癌、前列腺癌、胃癌中,35种miR过表达,14种减量调节(δ=0.9,FDR=0.001)。
表5.通过PAM(微阵列的预测分析)选择的微小RNA,6种实体癌类型相对于正常组织中*
*-T=1.5,误分类误差=0.176。正癌症评分指示36种在癌症中过表达的miR;负癌症评分指示21种减量调节的miR。
实施例2:与不同人实体癌有关的微小RNA表达特征的鉴定
结果
为了鉴定预示与实体瘤有关的癌症状态的微小RNA,而不招致由于组织特异性的偏倚,使用了一个替代方案。首先,通过进行独立的PAM检验(总结在表6和7中),得到6种组织-特异性的特征,每种对应一种癌症组织型。在表8-13中显示了每种癌症的特异性特征:例如,乳腺癌-表8;结肠癌-表9;肺癌-表10;胰腺癌-表11;前列腺癌-表12;胃癌-表13。使用这些数据,鉴定出在不同组织型miRNA特征之间共有的失调的微小RNA(表14)。为了计算用于该对比分析的p-值,进行对miRNA身份的1,000,000个随机置换的再取样检验。将p-值定义为超过实际评分的模拟评分的相对频率。鉴定出至少3类实体癌共有的21种错误调节的微小RNA(p-值=2.5 x 10-3)(表14)。表6.用于区分人癌症和正常组织的微小RNA*.
癌症 增量调节的miR 减量调节的miR 10倍交叉验证后的
错误分类误差
乳腺癌 15 12 0.08
结肠癌 21 1 0.09
肺癌 35 3 0.31
胰腺癌 55 2 0.02
前列腺癌 39 6 0.11
胃癌 22 6 0.19
*-进行中位值标准化,使用最近萎缩图心方法来选择预测性的miRNA.
表7.在实体普通癌中失调的微小RNA*。
*-微阵列的预测分析(PAM)鉴定出了最佳表征癌症和正常组织的那些基因,同时微阵列的显著性分析(SAM)鉴定出了在2类中具有差异表达的所有基因。在括号中标出了在SAM中计算的误检率(FDR)。
表8.通过微阵列的预测分析(PAM)在乳腺癌中选择的微小RNA(癌症相对于正常组织)*.
*27种选择的miR,在交叉验证后误分类误差为0.008。正癌症评分指示17种在癌症中过表达的miR;负癌症评分指示12种减量调节的miR。
表9.通过微阵列的预测分析(PAM)在结肠癌中选择的微小RNA(癌症相对于正常组织)*.
*22种选择的miR,在交叉验证后误分类误差为0.09。正癌症评分指示21种在癌症中过表达的miR;负癌症评分指示1种减量调节的miR。
表10.通过微阵列的预测分析(PAM)在肺癌中选择的微小RNA(癌症相对于正常组织)*。
*38种选择的miR,在交叉验证后误分类误差为0.31。正癌症评分指示35种在癌症中过表达的miR;负癌症评分指示3种减量调节的miR。
表11.通过微阵列的预测分析(PAM)在胰腺癌中选择的微小RNA(癌症相对于正常组织)*。
表11(续).通过微阵列的预测分析(PAM)在胰腺癌中选择的微小RNA(癌症相对于正常组织)*。
*57种选择的miR,在交叉验证后误分类误差为0.02。癌症中57种miR过表达和2种miR减量调节(分别由正评分和负评分指示)。
表12.通过微阵列的预测分析(PAM)在前列腺癌中选择的微小RNA(癌症相对于正常组织)*。
表12(续).通过微阵列的预测分析(PAM)在前列腺癌中选择的微小RNA(癌症相对于正常组织)*。
*-T=1,45种选择的miR,在交叉验证后误分类误差为0.11。正癌症评分指示39种在癌症中过表达的miR;负癌症评分指示6种减量调节的miR。
表13.通过微阵列的预测分析(PAM)在胃癌中选择的微小RNA(癌症相对于正常组织)*。
*-T=1,28种选择的miR,在交叉验证后误分类误差为0.19。正癌症评分指示22种在癌症中过表达的miR;负癌症评分指示6种减量调节的miR。
表14.6种实体癌的特征共有的微小RNA*。
miR 数量 肿瘤类型
miR-21 6 乳腺 结肠 肺 胰腺 前列腺 胃
miR-17-5p 5 乳腺 结肠 肺 胰腺 前列腺
miR-191 5 结肠 肺 胰腺 前列腺 胃
miR-29b-2 4 乳腺 结肠 胰腺 前列腺
miR-223 4 结肠 胰腺 前列腺 胃
miR-128b 3 结肠 肺 胰腺
miR-199a-1 3 肺 胰腺 前列腺
miR-24-1 3 结肠 胰腺 胃
miR-24-2 3 结肠 胰腺 胃
miR-146 3 乳腺 胰腺 前列腺
miR-155 3 乳腺 结肠 肺
miR-181b-1 3 乳腺 胰腺 前列腺
miR-20a 3 结肠 胰腺 前列腺
miR-107 3 结肠 胰腺 胃
miR-32 3 结肠 胰腺 前列腺
miR-92-2 3 胰腺 前列腺 胃
miR-214 3 胰腺 前列腺 胃
miR-30c 3 结肠 胰腺 前列腺
miR-25 3 胰腺 前列腺 胃
miR-221 3 结肠 胰腺 胃
miR-106a 3 结肠 胰腺 前列腺
*-列表包括3或多种(N)实体癌类型中的21种共同增量调节的微小RNA(p-值=2.5 x 10-3)。
为了最简洁,计算了6个癌症/正常对的失调miR的平均绝对表达水平。使用综合子集中的miR的表达水平,正确地分类不同的组织,无论疾病状态(图3)。
图4显示了相对于正常组织,不同肿瘤组织之间共同微小RNA的差异表达。树显示了根据miRNA子集中倍数变化的不同癌症类型。其中前列腺、结肠、胃和胰腺组织最相似,而肺和乳腺组织由相当不同的特征代表(图4)。该树清楚地显示了哪些miRNA与特定癌症组织型有关。
引入注目的是,miR-21,miR-191和miR-17-5p在所有(或5/6)考虑的肿瘤类型中显著过表达。据报道,miR-21在成胶质细胞瘤中过表达且具有抗细胞凋亡性质(Chan,J.A.,等人,Cancer Res.65:6029-6033(2005))。肺癌与乳腺癌共有它的特征的一部分,且与其它实体瘤共有一部分,包括miR-17/20/92,所有这三者都是活跃地与c-Myc协作以加速淋巴瘤生成的微小RNA簇的成员(He,L.,等人,Nature 435:828-833(2005))。这些微小RNA过表达的鉴定,是对我们的方案的非常好的证实。激活的第二个miRNA组包括miR-210和miR-213,以及miR-155,后者已经报道在大细胞淋巴瘤(Eis,P.S.,等人,Proc.Natl.Acad.Sci.USA 102:3627-3632(2005))、具有伯基特淋巴瘤的儿童(Metzler,M.,等人,Genes ChromosomesCancer 39:167-169(2004))和多种B细胞淋巴瘤(Kluiver,J,等人,J.Pathol.,在线电子版,July 22,2005)中扩增。这些微小RNA是在乳腺癌和肺癌中仅有的增量调节的。miR-218-2在结肠癌、胃癌、前列腺癌和胰腺癌中一致地减量调节,但是在肺癌和乳腺癌中则不然。
几个观察结果强化了这些结果。首先,在该研究中,测定大多数基因的前体前-miRNA和成熟miRNA的表达水平。注意到,除了miR-212和miR-128a以外,在所有其它的情况下,异常表达的区域是与有活性的基因产物相对应的区域。其次,如图3所示,综合子集中miRNA的表达变化在不同类型的癌症之间经常是单一的(即,减量或增量调节),这暗示着在人肿瘤发生中的共同机制。第三,通过12个乳腺样品(miR-125b,miR-145和miR-21;Iorio,M.V.,等人,Cancer Res.65:7065-7070(2005))和17个内分泌胰腺和正常样品(miR-103,miR-155和miR-204;数据未显示)的溶液杂交,验证了微阵列数据,这强烈证实了微阵列数据的准确性。
实施例3:在实体瘤中失调的微小RNA的预测靶的鉴定
材料和方法:
肿瘤抑制基因和癌基因靶预测
使用最近的TargetScan预测(2005年4月)来鉴定推定的微小RNA靶。它们主要包括Lewis等人报道的3′UTR靶(Lewis,B.P.,等人,Cell 120:15-20(2005)),其中的几个变化源自2005年4月UCSCGenome Browser更新的基因边界定义,所述UCSC Genome Browser将RefSeq mRNA作图到hg17人基因组集合。在推定的靶中,根据它们在可以在因特网站www.sanger.ac.uk/genetics/CGP/Census/得到或由OMIM报道在www.ncbi.nlm.nih.gov的Cancer Gene Census中的鉴定,标明已知的癌症基因(肿瘤抑制基因和癌基因)。
靶体外试验
对于萤光素酶报道分子测定,通过PCR,从人基因组DNA扩增预测与特定的癌症相关微小RNA相互作用的Rb1、TGFBR2和Plag1的3′UTR区段,并使用在紧邻萤光素酶终止密码子下游的XbaI位点,插入pGL3对照载体(Promega)。在37℃、在5% CO2的控湿气氛下,使人巨核细胞系MEG-01生长在于RPMI培养基1640中的10%FBS中,其中添加了1x非必需氨基酸和1mmol丙酮酸钠。根据生产商的手册,使用siPORT neoFX(Ambion,Austin,TX),使用0.4μg的萤火虫萤光素酶报道载体和0.08μg的含有花虫萤光素酶的对照载体pRL-TK(Promega),将细胞共转染进12-孔平板。对于每个孔,使用浓度为10nM的微小RNA寡核苷酸(Dharmacon Research,Lafayette,CO)和反义或混杂的寡核苷酸(Ambion)。使用双-萤光素酶测定(Promega),在转染后24小时,连续测量萤火虫和花虫萤光素酶活性。
RB1的蛋白印迹
使用蛋白印迹的标准方法,使用小鼠单克隆抗-RB1抗体(SantaCruz,CA),定量RB1蛋白的水平。用小鼠单克隆抗-肌动蛋白抗体(Sigma)进行标准化。
结果
需要理解微小RNA失调在癌症中的功能意义。在实体瘤中,最常见的微小RNA事件似乎是表达的获得,而在癌症中表达的丧失是一种更有限的事件,且是更组织特异性的。我们使用了一个下述次序的三步骤因果方案:首先是靶的“计算机(insilico)”预测,然后是癌症相关靶的初次验证的萤光素酶测定,最后是特定miRNA:mRNA相互作用物对的miRNA表达(通过微阵列)和靶蛋白表达(通过蛋白印迹)之间的离体肿瘤关联。癌症miRNA的相关靶可以是隐性的(例如肿瘤抑制基因)或显性的(例如癌基因)癌症基因。为了测试下述假说,即在实体瘤中失调的微小RNA靶向已知的癌基因或肿瘤抑制基因,使用TargetScan,即保守的3’UTR微小RNA靶的数据库,确定这些miRNA的预测靶(Lewis,B.P.,等人,Cell 120:15-20(2005))。TargetScan在共22,402个预测中含有在实体瘤中失调的18种miRNA的5,121个预测(26.5%)。115/263个(44%)众所周知的癌症基因被预测为这18种miRNA的靶(表15)。因为高百分比的癌症基因被在实体瘤中失调的miR靶向,这些预测不可能是由于偶然(在Fisher精确检验中,P<0.0001)。
通过体外测定,实验证实了3种不同癌症基因-视网膜母细胞瘤(Rb)、TGF-β-2受体(TGFBR2)和多形腺瘤基因1(PLAG1)的计算机预测。使用萤光素酶报道分子测定,在转染的MEG-01细胞中与混杂的对照寡RNA相比,测试的3种微小RNA(miR-106a,miR-20a和miR-26a-1)造成了蛋白翻译的显著降低(图6)。例如,发现视网膜母细胞瘤3’UTR在功能上与miR-106a相互作用。以前的报道表明,Rb1基因在结肠癌中正常转录,而多个部分的细胞不表达Rb1蛋白,这强化了该miRNA:mRNA相互作用的生物学重要性(Ali,A.A.,等人,FASEBJ.7:931-937(1993))。该发现暗示着调节Rb1的转录后机制的存在,这可以通过结肠癌中伴随的miR-106a过表达来解释(图4)。此外,mir-20a在乳腺癌中减量调节(图4),TFGBR2蛋白在乳腺癌细胞上皮中表达(Buck,M.B.,等人,Clin.Cancer Res.10:491-498(2004))。反之,mir-20a在结肠癌中的过表达可以代表除了突变失活以外的减量调节TGFBR2的新颖机制(Biswas,S.,等人,Cancer Res.64:687-692(2004))。
最后,测试了一组患者样品,以验证RB1蛋白表达是否与miR-106a表达相关联(图5和图6B)。如预期的,在胃、前列腺和肺肿瘤样品中,RB1减量调节(相对于配对的正常样品),且发现miR-106a过表达;而在乳腺肿瘤样品中,miR-106a轻微减量调节(图5和图6B),且RB1以比配对的正常对照略高的水平表达。
这些实验证据强化了下述假说,即实体癌中的关键癌症基因由miR的异常表达调节。这些数据为如以前由Johnsson等人(Johnson,S.M.,等人,Cell 120:635-647(2005))(关于let-7:Ras相互作用)、O’Donnell等人(O′Donnell,K.A.,等人,Nature 435:839-843(2005))(关于miR-17-5p:cMyc相互作用)和Cimmino等人(Cimmino,A.,等人,Proc.Natl.Acad.Sci.USA 102:13944-13949(2005))(关于mir-16:Bc12相互作用)所示的具有重要癌症基因靶的微小RNA列表增加了新的实例,。值得注意地,miR-17-5p和miR-16是本文所述的miRNA实体癌特征的成员。
表15.由综合癌症子集通过TargetScanS预测为微小RNA的靶的癌基因和肿瘤抑制基因。*
*-已知的癌症基因(例如肿瘤抑制基因,癌基因)包含在www.sanger.ac.uk/genetics/CGP/Census/或由OMIM报道在www.ncbi.nlm.nih.gov的Cancer Gene Census中鉴定的那些。
未明确通过参考引用并入的本文引述的所有出版物的相关教导整体通过参考引用并入本文。尽管参考其优选实施方案已具体地显示和描述了本发明,但本领域技术人员将理解其中可进行形式和细节上的多种不同变化,而不偏离所附权利要求包括的本发明的范围。
Claims (33)
1.诊断受试者是否患有实体癌或处于发生实体癌的风险中的方法,其包括,测量来自受试者的测试样品中至少一种miR基因产物的水平,其中与对照样品中相应的miR基因产物的水平相比,测试样品中所述miR基因产物的水平的改变,指示着受试者患有实体癌或处于发生实体癌的风险中。
2.权利要求1的方法,其中所述至少一种miR基因产物选自:miR-21,miR-191,miR-17-5p和其组合。
3.权利要求1的方法,其中所述至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
4.权利要求1的方法,其中所述实体癌选自:前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌和结肠癌。
5.权利要求1的方法,其中所述实体癌是乳腺癌或肺癌,且所述至少一种miR基因产物选自:miR-210,miR-213和其组合。
6.权利要求1的方法,其中所述实体癌是结肠癌,胃癌,前列腺癌,或胰腺癌,且所述至少一种miR基因产物是miR-218-2。
7.权利要求1的方法,其中所述实体癌是乳腺癌,且所述至少一种miR基因产物选自:miR-125b-1,miR125b-2,miR-145,miR-21和其组合。
8.权利要求1的方法,其中所述实体癌是胰腺癌,且所述至少一种miR基因产物选自:miR-103-1,miR-103-2,miR-155,miR-204和其组合。
9.权利要求1的方法,其中所述实体癌和所述至少一种miR基因产物选自:
(i)所述实体癌是乳腺癌,且所述miR基因产物选自:miR-21,miR-29b-2,miR-146,miR-125b-2,miR-125b-1,miR-10b,miR-145,miR-181a,miR-140,miR-213,miR-29a prec,miR-181b-1,miR-199b,miR-29b-1,miR-130a,miR-155,let-7a-2,miR-205,miR-29c,miR-224,miR-100,miR-31,miR-30c,miR-17-5p,miR-210,miR-122a,miR-16-2和其组合;
(ii)所述实体癌是结肠癌,且所述miR基因产物选自:miR-24-1,miR-29b-2,miR-20a,miR-10a,miR-32,miR-203,miR-106a,miR-17-5p,miR-30c,miR-223,miR-126*,miR-128b,miR-21,miR-24-2,miR-99b prec,miR-155,miR-213,miR-150,miR-107,miR-191,miR-221,miR-9-3和其组合;
(iii)所述实体癌是肺癌,且所述miR基因产物选自:miR-21,miR-205,miR-200b,miR-9-1,miR-210,miR-148,miR-141,miR-132,miR-215,miR-128b,let-7g,miR-16-2,miR-129-1/2prec,miR-126*,miR-142-as,miR-30d,miR-30a-5p,miR-7-2,miR-199a-1,miR-127,miR-34a prec,miR-34a,miR-136,miR-202,miR-196-2,miR-199a-2,let-7a-2,miR-124a-1,miR-149,miR-17-5p,miR-196-1 prec,miR-10a,miR-99b prec,miR-196-1,miR-199b,miR-191,miR-195,miR-155和其组合;
(iv)所述实体癌是胰腺癌,且所述miR基因产物选自:miR-103-2,miR-103-1,miR-24-2,miR-107,miR-100,miR-125b-2,miR-125b-1,miR-24-1,miR-191,miR-23a,miR-26a-1,miR-125a,miR-130a,miR-26b,miR-145,miR-221,miR-126*,miR-16-2,miR-146,miR-214,miR-99b,miR-128b,miR-155,miR-29b-2,miR-29a,miR-25,miR-16-1,miR-99a,miR-224,miR-30d,miR-92-2,miR-199a-1,miR-223,miR-29c,miR-30b,miR-129-1/2,miR-197,miR-17-5p,miR-30c,miR-7-1,miR-93-1,miR-140,miR-30a-5p,miR-132,miR-181b-1,miR-152 prec,miR-23b,miR-20a,miR-222,miR-27a,miR-92-1,miR-21,miR-129-1/2 prec,miR-150,miR-32,miR-106a,miR-29b-1和其组合;
(v)所述实体癌是前列腺癌,且所述miR基因产物选自:let-7d,miR-128a prec,miR-195,miR-203,let-7a-2 prec,miR-34a,miR-20a,miR-218-2,miR-29a,miR-25,miR-95,miR-197,miR-135-2,miR-187,miR-196-1,miR-148,miR-191,miR-21,let-7i,miR-198,miR-199a-2,miR-30c,miR-17-5p,miR-92-2,miR-146,miR-181b-1 prec,miR-32,miR-206,miR-184 prec,miR-29a prec,miR-29b-2,miR-149,miR-181b-1,miR-196-1 prec,miR-93-1,miR-223,miR-16-1,miR-101-1,miR-124a-1,miR-26a-1,miR-214,miR-27a,miR-24-1,miR-106a,miR-199a-1和其组合;和
(vi)所述实体癌是胃癌,且所述miR基因产物选自:miR-223,miR-21,miR-218-2,miR-103-2,miR-92-2,miR-25,miR-136,miR-191,miR-221,miR-125b-2,miR-103-1,miR-214,miR-222,miR-212 prec,miR-125b-1,miR-100,miR-107,miR-92-1,miR-96,miR-192,miR-23a,miR-215,miR-7-2,miR-138-2,miR-24-1,miR-99b,miR-33b,miR-24-2和其组合。
10.诊断受试者是否患有实体癌或处于发生实体癌的风险中的方法,其包括:
(1)从获自受试者的测试样品逆转录RNA,以提供一组靶寡脱氧核苷酸;
(2)使所述靶寡脱氧核苷酸与包含miRNA-特异性探针寡核苷酸的微阵列杂交,以提供测试样品的杂交谱;和
(3)对比测试样品杂交谱与从对照样品产生的杂交谱,
其中至少一种miRNA的信号的改变指示着受试者患有实体癌或处于发生实体癌的风险中。
11.权利要求10的方法,其中与从对照样品产生的信号相比,至少一种miRNA的信号降低。
12.权利要求10的方法,其中与从对照样品产生的信号相比,至少一种miRNA的信号增加。
13.权利要求10的方法,其中所述微阵列包含针对选自下述的一种或多种miRNA的miRNA-特异性探针寡核苷酸:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
14.抑制患有或被怀疑患有实体癌的受试者的肿瘤发生的方法,其中与对照细胞相比,受试者癌细胞中的至少一种miR基因产物被减量调节或增量调节,该方法包括:
(1)当癌细胞中的至少一种miR基因产物被减量调节时,给受试者施用有效量的至少一种分离的miR基因产物、或其分离的变体或生物活性片段,条件是,所述miR基因产物不是miR-15a或miR-16-1,从而抑制受试者中的肿瘤发生;或
(2)当癌细胞中的至少一种miR基因产物被增量调节时,给受试者施用有效量的至少一种用于抑制所述至少一种miR基因产物的表达的化合物,从而抑制受试者中的肿瘤发生。
15.权利要求14的方法,其中步骤(1)中的至少一种分离的miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
16.权利要求14的方法,其中步骤(2)中的至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
17.权利要求14的方法,其中所述实体癌选自:前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌和结肠癌。
18.抑制患有实体癌的受试者的肿瘤发生的方法,其包括:
(1)测定与对照细胞相比,受试者癌细胞中至少一种miR基因产物的量;和
(2)通过下述方式,改变在癌细胞中表达的miR基因产物的量:
(i)如果在癌细胞中表达的miR基因产物的量小于在对照细胞中表达的miR基因产物的量,给受试者施用有效量的至少一种分离的miR基因产物、或其分离的变体或生物活性片段,条件是,所述miR基因产物不是miR-15a或miR-16-1;或
(ii)如果在癌细胞中表达的miR基因产物的量大于在对照细胞中表达的miR基因产物的量,给受试者施用有效量的至少一种用于抑制所述至少一种miR基因产物的表达的化合物,
从而抑制受试者中的肿瘤发生。
19.权利要求18的方法,其中步骤(i)中的至少一种分离的miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
20.权利要求18的方法,其中步骤(ii)中的至少一种miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
21.用于治疗实体癌的药物组合物,其包含至少一种分离的miR基因产物、或其分离的变体或生物活性片段,和药学上可接受的载体。
22.权利要求21的药物组合物,其中所述至少一种分离的miR基因产物对应于相对于合适的对照细胞在癌细胞中减量调节的miR基因产物。
23.权利要求22的药物组合物,其中所述分离的miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
24.权利要求21的药物组合物,其中所述实体癌选自:前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌和结肠癌。
25.用于治疗实体癌的药物组合物,其包含至少一种抑制miR表达的化合物和药学上可接受的载体。
26.权利要求25的药物组合物,其中所述至少一种抑制miR表达的化合物对相对于合适的对照细胞在癌细胞中增量调节的miR基因产物是特异性的。
27.权利要求26的药物组合物,其中所述至少一种抑制miR表达的化合物对选自下述的miR基因产物是特异性的:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
28.鉴定肿瘤发生抑制剂的方法,其包括给细胞提供测试试剂,并测量与实体癌中降低的表达水平有关的至少一种miR基因产物的水平,其中与合适的对照细胞相比,所述细胞中所述miR基因产物的水平的增加,指示着测试试剂是肿瘤发生抑制剂。
29.权利要求29的方法,其中所述miR基因产物选自:miR-145,miR-155,miR-218-2和其组合。
30.权利要求29的方法,其中所述实体癌选自:前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌和结肠癌。
31.鉴定肿瘤发生抑制剂的方法,其包括给细胞提供测试试剂,并测量与实体癌中增加的表达水平有关的至少一种miR基因产物的水平,其中与合适的对照细胞相比,所述细胞中所述miR基因产物的水平的降低,指示着测试试剂是肿瘤发生抑制剂。
32.权利要求32的方法,其中所述miR基因产物选自:miR-21,miR-17-5p,miR-191,miR-29b-2,miR-223,miR-128b,miR-199a-1,miR-24-1,miR-24-2,miR-146,miR-155,miR-181b-1,miR-20a,miR-107,miR-32,miR-92-2,miR-214,miR-30c,miR-25,miR-221,miR-106a和其组合。
33.权利要求32的方法,其中所述实体癌选自:前列腺癌,胃癌,胰腺癌,肺癌,乳腺癌和结肠癌。
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CN101942502A (zh) * | 2009-12-24 | 2011-01-12 | 北京命码生科科技有限公司 | 胰腺癌标记物及其检测方法、试剂盒和生物芯片 |
CN101988061A (zh) * | 2009-07-30 | 2011-03-23 | 江苏命码生物科技有限公司 | 乳腺癌检测标记物及其检测方法、试剂盒和生物芯片 |
CN102018965A (zh) * | 2010-09-17 | 2011-04-20 | 天津医科大学 | miRNA-10a在制备抑制结肠癌的侵袭和转移药物中的应用 |
CN102031261A (zh) * | 2010-10-27 | 2011-04-27 | 南京医科大学 | 一种与妊娠期糖尿病相关的血清/血浆miRNA标志物及其应用 |
WO2011075873A1 (zh) * | 2009-12-24 | 2011-06-30 | 北京命码生科科技有限公司 | 胰腺癌标记物及其检测方法、试剂盒和生物芯片 |
WO2011076144A1 (en) * | 2009-12-24 | 2011-06-30 | Fudan University | Compositions and methods for microrna expession profiling in plasma of lung cancer |
WO2011076145A1 (en) * | 2009-12-24 | 2011-06-30 | Fudan University | Tissue-based micro-rna methods for diagnosis of different subtypes of lung cancer |
CN102140467A (zh) * | 2010-12-30 | 2011-08-03 | 苏州吉玛基因股份有限公司 | 人miR-365反义核酸及其应用 |
CN102140466A (zh) * | 2010-12-30 | 2011-08-03 | 苏州吉玛基因股份有限公司 | 人miR-1825反义核酸及其应用 |
CN102146412A (zh) * | 2011-01-11 | 2011-08-10 | 中山大学 | 一种小分子非编码RNA基因hsa-miR-29b及其应用 |
CN102242080A (zh) * | 2010-05-13 | 2011-11-16 | 北京大学第三医院 | miR-24用于治疗或诊断心衰或患心衰倾向或者改善心肌细胞功能的方法 |
WO2011150855A1 (en) * | 2010-06-04 | 2011-12-08 | Fudan University | Micro-rna biomarkers and methods for diagnosis of early colorectal carcinoma and high-grade adenoma |
CN102406653A (zh) * | 2010-09-21 | 2012-04-11 | 中国人民解放军第二军医大学 | 一种miRNA的抗病毒作用、实施方法及用途 |
CN102443644A (zh) * | 2011-12-20 | 2012-05-09 | 苏州福英基因科技有限公司 | 结肠癌病理演变前期microrna-29a水平原位杂交检测试剂盒及检测方法和应用 |
CN102533978A (zh) * | 2011-12-15 | 2012-07-04 | 苏州福英基因科技有限公司 | 各种癌症病理演变前期microrna-373水平原位杂交检测试剂盒及检测方法和应用 |
CN102533976A (zh) * | 2011-12-15 | 2012-07-04 | 苏州福英基因科技有限公司 | 各种癌症病理演变前期microrna-21原位杂交检测试剂盒及检测方法和应用 |
CN102533983A (zh) * | 2011-12-19 | 2012-07-04 | 苏州福英基因科技有限公司 | 癌症病理演变前期microrna-330水平原位杂交检测试剂盒及检测方法和应用 |
CN102533980A (zh) * | 2011-12-15 | 2012-07-04 | 苏州福英基因科技有限公司 | 各种癌症病理演变前期microrna-10b水平原位杂交检测试剂盒及检测方法和应用 |
CN102533977A (zh) * | 2011-12-15 | 2012-07-04 | 苏州福英基因科技有限公司 | 各种癌症病理演变前期microrna-372水平原位杂交检测试剂盒及检测方法和应用 |
CN102559884A (zh) * | 2011-12-27 | 2012-07-11 | 芮屈生物技术(上海)有限公司 | 各种癌症病理演变前期let-7mirna水平原位杂交检测试剂盒及检测方法和应用 |
CN102676524A (zh) * | 2012-05-16 | 2012-09-19 | 北京旷博生物技术有限公司 | 乳腺癌分子标志物miR-147a |
CN102743765A (zh) * | 2012-05-24 | 2012-10-24 | 上海大学 | 非小细胞肺癌中miR-10a基因的应用 |
CN102770561A (zh) * | 2009-12-24 | 2012-11-07 | 复旦大学 | 用于诊断不同亚型肺癌的基于组织的微-rna方法 |
CN102827943A (zh) * | 2012-09-19 | 2012-12-19 | 南开大学 | miRNA 320a在前列腺癌血清学诊断试剂盒中的应用 |
CN103224933A (zh) * | 2013-02-22 | 2013-07-31 | 上海大学 | 非小细胞肺癌中miR-34a基因的应用 |
WO2013155980A1 (zh) * | 2012-04-19 | 2013-10-24 | 中国科学院上海生命科学研究院 | 自身免疫性疾病相关的microRNA及其应用 |
CN103740848A (zh) * | 2014-01-28 | 2014-04-23 | 厦门大学附属中山医院 | 基于AllGlo探针荧光定量PCR的hsa-miR-146检测试剂盒及其检测方法 |
CN103805603A (zh) * | 2014-01-20 | 2014-05-21 | 南京医科大学附属南京儿童医院 | 与常见型先天肠管无神经节细胞症发生相关的血浆miRNA标志物及其应用 |
CN105219867A (zh) * | 2015-11-02 | 2016-01-06 | 杨廷稳 | 用于胃癌诊断的miRNA生物标志物及检测试剂盒 |
CN105238863A (zh) * | 2015-10-29 | 2016-01-13 | 中国科学院近代物理研究所 | miR-197在作为肝癌检测标志物中的应用 |
CN105441448A (zh) * | 2015-11-26 | 2016-03-30 | 中国农业科学院北京畜牧兽医研究所 | miR-192对绵羊骨骼肌卫星细胞增殖分化调控应用 |
CN105497900A (zh) * | 2015-04-30 | 2016-04-20 | 苏州大学 | 一种抗未分化甲状腺癌耐药靶点及其应用 |
CN105586401A (zh) * | 2015-12-14 | 2016-05-18 | 常州杰傲医学检验所有限公司 | 一种用于乳腺癌诊断的miRNA标志物、其应用及诊断试剂盒 |
US9388470B2 (en) | 2008-12-15 | 2016-07-12 | Micromedmark Biotech Co., Ltd. | Serum or plasma microRNA as biomarkers for non-small cell lung cancer |
CN105779579A (zh) * | 2015-01-09 | 2016-07-20 | 长庚大学 | 评估罹患结肠直肠癌风险的方法及标志物 |
CN105779580A (zh) * | 2015-01-09 | 2016-07-20 | 长庚大学 | 评估罹患结肠直肠癌风险的方法及标志物 |
CN107250378A (zh) * | 2015-02-24 | 2017-10-13 | 株式会社遗传科技 | 癌的脑转移的诊断、预防及治疗方法、以及用于通过血脑屏障的药物传输系统 |
CN107488734A (zh) * | 2017-10-10 | 2017-12-19 | 广州医科大学附属第二医院 | miR‑19a‑3p在制备前列腺癌骨转移诊断试剂和治疗药物中的应用 |
CN107746886A (zh) * | 2017-09-11 | 2018-03-02 | 朱伟 | 一种与结直肠癌辅助诊断相关的血浆miRNA标志物及其应用 |
CN107810278A (zh) * | 2015-06-18 | 2018-03-16 | 大邱庆北科学技术院 | 利用微rna与n‑甲基‑d‑天冬氨酸受体的相关关系的海马体的功能下降的判断方法、功能下降的抑制方法及功能下降抑制剂的筛选方法 |
CN107815492A (zh) * | 2017-12-08 | 2018-03-20 | 武汉科技大学 | 一种基于qpcr诊断乳腺癌的检测方法 |
CN107904301A (zh) * | 2017-10-26 | 2018-04-13 | 宁波市微循环与莨菪类药研究所 | miR‑181a作为海洛因成瘾的生物标记物及其在制备抗海洛因复吸药物中的应用 |
CN108559773A (zh) * | 2018-04-18 | 2018-09-21 | 江苏省人民医院(南京医科大学第附属医院) | miR-218在制备治疗骨质疏松症药物中的应用 |
CN109971851A (zh) * | 2019-01-22 | 2019-07-05 | 宁波大学 | MiR-125b-2-3p作为鉴别诊断肾癌亚型的分子标志物及其在肿瘤转移中的用途 |
CN110354137A (zh) * | 2019-08-20 | 2019-10-22 | 中山大学附属第六医院 | miRNA-197-3p在制备抗前列腺癌药物中的应用 |
CN111944809A (zh) * | 2020-07-28 | 2020-11-17 | 武汉睿健医药科技有限公司 | 帕金森病的诊断标志物及其应用 |
CN112048554A (zh) * | 2020-06-29 | 2020-12-08 | 浙江大学 | 脂质体纳米颗粒芯片及其在制备胰腺癌诊断产品中的应用和相应标志物 |
WO2021218592A1 (zh) * | 2020-04-29 | 2021-11-04 | 康德(深圳)生物技术有限公司 | 用于早期胰腺肿瘤检测分子标志物、其检测方法及应用 |
Families Citing this family (245)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005013901A2 (en) | 2003-07-31 | 2005-02-17 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and compositions for use in modulation of small non-coding rnas |
EP2295604B1 (en) | 2004-02-09 | 2015-04-08 | Thomas Jefferson University | Diagnosis and treatment of cancers with microRNA located in or near cancer-associated chromosomal features |
EP2290071B1 (en) | 2004-05-28 | 2014-12-31 | Asuragen, Inc. | Methods and compositions involving microRNA |
EP2281888B1 (en) | 2004-11-12 | 2015-01-07 | Asuragen, Inc. | Methods and compositions involving miRNA and miRNA inhibitor molecules |
WO2006133022A2 (en) * | 2005-06-03 | 2006-12-14 | The Johns Hopkins University | Compositions and methods for decreasing microrna expression for the treatment of neoplasia |
CA2617581A1 (en) | 2005-08-01 | 2007-02-08 | The Ohio State University Research Foundation | Microrna-based methods for the diagnosis of breast cancer |
ES2523989T3 (es) | 2005-09-12 | 2014-12-03 | The Ohio State University Research Foundation | Composiciones para la terapia de cánceres asociados con BCL2 |
US8445198B2 (en) * | 2005-12-01 | 2013-05-21 | Medical Prognosis Institute | Methods, kits and devices for identifying biomarkers of treatment response and use thereof to predict treatment efficacy |
CN102943108B (zh) | 2006-01-05 | 2014-05-21 | 俄亥俄州立大学研究基金会 | 用于肺癌的诊断、预后和治疗的基于微小rna的方法和组合物 |
EP1968622B1 (en) | 2006-01-05 | 2014-08-27 | The Ohio State University Research Foundation | Microrna expression abnormalities in pancreatic endocrine and acinar tumors |
ES2461189T3 (es) * | 2006-01-05 | 2014-05-19 | The Ohio State University Research Foundation | Métodos basados en microARN y composiciones para el diagnóstico y el tratamiento de cánceres sólidos de mama o pulmón |
EP2369012A1 (en) * | 2006-03-20 | 2011-09-28 | The Ohio State University Research Foundation | Micro-RNA fingerprints during human megakaryocytopoiesis |
ES2425387T3 (es) | 2006-07-13 | 2013-10-15 | The Ohio State University Research Foundation | Mir-106a para diagnosticar adenocarcinoma de colon de pronóstico de supervivencia pobre |
WO2008097277A2 (en) | 2006-09-19 | 2008-08-14 | The Ohio State University Research Foundation | Tcl1 expression in chronic lymphocytic leukemia (cll) regulated by mir-29 and mir-181 |
AU2007314212B2 (en) | 2006-11-01 | 2014-05-29 | The Govt. Of The Usa As Represented By The Secretary Of The Department Of Health And Human Services | MicroRNA expression signature for predicting survival and metastases in Hepatocellular carcinoma |
US8975026B2 (en) * | 2007-01-16 | 2015-03-10 | Somalogic, Inc. | Method for generating aptamers with improved off-rates |
US8034560B2 (en) | 2007-01-31 | 2011-10-11 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of acute myeloid leukemia (AML) |
CA2685840C (en) * | 2007-04-30 | 2016-12-13 | The Ohio State University Research Foundation | Methods for differentiating pancreatic cancer from normal pancreatic function and/or chronic pancreatitis |
US8697672B2 (en) * | 2007-05-16 | 2014-04-15 | California Institute Of Technology | Microrna inhibition for the treatment of inflammation and myeloproliferative disorders |
US20100298158A1 (en) * | 2007-05-21 | 2010-11-25 | Dana-Farber Cancer Institute, Inc. | Compositions, Kits, and Methods for Identification, Assessment, Prevention, and Therapy of Cancer |
ES2527648T3 (es) | 2007-06-08 | 2015-01-28 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Métodos para determinar el subtipo de carcinoma hepatocelular |
CN101918424A (zh) | 2007-06-15 | 2010-12-15 | 俄亥俄州立大学研究基金会 | 用于靶向由Drosha介导的微小RNA加工的致癌ALL-1融合蛋白 |
US20130190379A1 (en) * | 2007-07-06 | 2013-07-25 | Edwin Pieter Johan Cuppen | Small rna molecules, precursors thereof, means and methods for detecting them, and uses thereof in typing samples |
WO2009015071A1 (en) * | 2007-07-23 | 2009-01-29 | Dharmacon, Inc. | Screening of micro-rna cluster inhibitor pools |
CN101809169B (zh) | 2007-07-31 | 2013-07-17 | 俄亥俄州立大学研究基金会 | 通过靶向dnmt3a和dnmt3b恢复甲基化的方法 |
NZ583024A (en) | 2007-07-31 | 2012-04-27 | Regents The Univeristy Of Texas System Board Of | An agonist of miR-29a, miR-29b or miR-29c that prevents tissue fibrosis and uses thereof |
ES2627059T3 (es) | 2007-08-03 | 2017-07-26 | The Ohio State University Research Foundation | Regiones ultraconservadas que codifican ARNnc |
WO2009021235A2 (en) * | 2007-08-09 | 2009-02-12 | The Regents Of The University Of Colorado | Methods and compositions for treating cancer |
US8716255B2 (en) | 2007-08-10 | 2014-05-06 | British Columbia Cancer Agency Branch | Microrna compositions and methods for the treatment of myelogenous leukemia |
JP5770472B2 (ja) | 2007-08-22 | 2015-08-26 | ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイションThe Ohio State University Research Foundation | ヒト急性白血病におけるepha7及びerkリン酸化の調節解除を誘発するための方法及び組成物 |
WO2009024790A1 (en) * | 2007-08-23 | 2009-02-26 | Isis Innovation Limited | Method and kit for the prognosis of cancer by determining the level of mirna-210 |
CN101939446B (zh) * | 2007-09-06 | 2015-02-11 | 俄亥俄州立大学研究基金会 | 人类卵巢癌中的微小rna特征 |
WO2009036332A1 (en) | 2007-09-14 | 2009-03-19 | Asuragen, Inc. | Micrornas differentially expressed in cervical cancer and uses thereof |
ES2575868T3 (es) * | 2007-09-14 | 2016-07-01 | The Ohio State University Research Foundation | Expresión de miARN en microvesículas de sangre periférica humana y sus usos |
US20090136957A1 (en) * | 2007-09-15 | 2009-05-28 | Irena Ivanovska | Methods and compositions for regulating cell cycle progression via the miR-106B family |
WO2009044899A1 (ja) * | 2007-10-03 | 2009-04-09 | Kyowa Hakko Kirin Co., Ltd. | 細胞の増殖を制御する核酸 |
WO2009055773A2 (en) | 2007-10-26 | 2009-04-30 | The Ohio State University Research Foundation | Methods for identifying fragile histidine triad (fhit) interaction and uses thereof |
MX2010004916A (es) | 2007-10-30 | 2010-05-20 | Veridex Llc | Proceso para predecir el pronostico de cancer en celulas escamosas de pulmon. |
CN101424640B (zh) * | 2007-11-02 | 2012-07-25 | 江苏命码生物科技有限公司 | 血清中微小核糖核酸的检测方法和用于检测的试剂盒、生物芯片及其制作和应用方法 |
US8071562B2 (en) | 2007-12-01 | 2011-12-06 | Mirna Therapeutics, Inc. | MiR-124 regulated genes and pathways as targets for therapeutic intervention |
WO2009085234A2 (en) * | 2007-12-20 | 2009-07-09 | Signal Pharmaceuticals, Inc. | Use of micro-rna as a biomarker of immunomodulatory drug activity |
WO2009082744A2 (en) * | 2007-12-22 | 2009-07-02 | Sloan-Kettering Institute For Cancer Research | Prognosis and interference-mediated treatment of breast cancer |
JP5116026B2 (ja) * | 2008-01-23 | 2013-01-09 | 富士フイルム株式会社 | 癌の検出方法および癌抑制剤 |
CN102007223B (zh) * | 2008-02-28 | 2014-06-18 | 俄亥俄州立大学研究基金会 | 用于胃癌的诊断、预后和治疗的基于微rna的方法和组合物 |
EP3112477A1 (en) * | 2008-02-28 | 2017-01-04 | The Ohio State University Research Foundation | Microrna-based methods and compositions for the diagnosis, prognosis and treatment of prostate related disorders |
WO2009111643A2 (en) * | 2008-03-06 | 2009-09-11 | Asuragen, Inc. | Microrna markers for recurrence of colorectal cancer |
US8258111B2 (en) | 2008-05-08 | 2012-09-04 | The Johns Hopkins University | Compositions and methods related to miRNA modulation of neovascularization or angiogenesis |
WO2009143379A2 (en) * | 2008-05-21 | 2009-11-26 | Fred Hutchinson Cancer Research Center | Use of extracellular rna to measure disease |
EP2123258A1 (en) | 2008-05-23 | 2009-11-25 | Liplasome Pharma A/S | Liposomes for drug delivery |
US9217155B2 (en) | 2008-05-28 | 2015-12-22 | University Of Massachusetts | Isolation of novel AAV'S and uses thereof |
AU2009253675A1 (en) | 2008-05-28 | 2009-12-03 | Genomedx Biosciences, Inc. | Systems and methods for expression-based discrimination of distinct clinical disease states in prostate cancer |
US9765334B2 (en) * | 2008-06-01 | 2017-09-19 | Rosetta Genomics, Ltd. | Compositions and methods for prognosis of gastric cancer |
EP2307028B1 (en) | 2008-06-11 | 2013-10-02 | The Government of the United States of America as represented by The Secretary of the Department of Health and Human Services | Use of mir-26 family as a predictive marker of hepatocellular carcinoma and responsiveness to therapy |
AU2009303690B2 (en) * | 2008-09-26 | 2014-06-19 | Tocagen Inc. | Gene therapy vectors and cytosine deaminases |
WO2010050328A1 (ja) * | 2008-10-27 | 2010-05-06 | 国立がんセンター総長が代表する日本国 | 腫瘍の転移抑制剤 |
GB2465088C (en) * | 2008-10-30 | 2016-01-27 | Caris Mpi Inc | miRNA expression in the characterisation and classification of cancer |
CA2742324A1 (en) | 2008-10-30 | 2010-06-03 | Caris Life Sciences Luxembourg Holdings, S.A.R.L. | Methods for assessing rna patterns |
US9074206B2 (en) | 2008-11-13 | 2015-07-07 | Fudan University | Compositions and methods for micro-RNA expression profiling of colorectal cancer |
WO2010058393A2 (en) * | 2008-11-20 | 2010-05-27 | Rosetta Genomics Ltd. | Compositions and methods for the prognosis of colon cancer |
CA2745919A1 (en) * | 2008-12-05 | 2010-06-10 | Whitehead Institute For Biomedical Research | Compositions and methods relating to mir-31 |
JP2012510813A (ja) * | 2008-12-05 | 2012-05-17 | ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション | 卵巣癌の診断および治療のためのマイクロrnaに基づく方法および組成物 |
EP2199412A1 (en) * | 2008-12-10 | 2010-06-23 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Compositions and methods for micro-RNA expression profiling of cancer stem cells |
EP2358902A1 (en) * | 2008-12-10 | 2011-08-24 | Universität Regensburg | Compositions and methods for micro-rna expression profiling of cancer stem cells |
EP2196542A1 (en) * | 2008-12-15 | 2010-06-16 | Koninklijke Philips Electronics N.V. | Compositions and methods for micro-rna expression profiling of colorectal cancer |
US8492133B2 (en) | 2009-01-20 | 2013-07-23 | Ramot At Tel Aviv University, Ltd. | MIR-21 promoter driven targeted cancer therapy |
WO2010094155A1 (en) * | 2009-02-23 | 2010-08-26 | Capitalbio Corporation | Methods and compositions diagnosing lung cancer, determining prognosis, and improving patient survival |
EP2401406A4 (en) * | 2009-02-25 | 2012-09-19 | Cepheid | METHODS OF DETECTING LUNG CANCER |
US8785414B2 (en) | 2009-03-31 | 2014-07-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Differentially expressed microRNAs as biomarkers for the diagnosis and treatment of Sjögren's syndrome |
WO2010119698A1 (ja) * | 2009-04-16 | 2010-10-21 | 学校法人 慶應義塾 | 頭頸部腫瘍増殖抑制剤 |
CN102596255B (zh) | 2009-04-30 | 2017-10-13 | 圣拉法埃莱医院有限公司 | 基因载体 |
WO2010135692A2 (en) * | 2009-05-22 | 2010-11-25 | Asuragen, Inc. | Mirna biomarkers of prostate disease |
WO2010138263A2 (en) | 2009-05-28 | 2010-12-02 | University Of Massachusetts | Novel aav 's and uses thereof |
US20100322909A1 (en) | 2009-06-17 | 2010-12-23 | The University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Th1-associated micrornas and their use for tumor immunotherapy |
WO2011017089A1 (en) * | 2009-07-27 | 2011-02-10 | The Regents Of The University Of Colorado, A Body Corporate | Mirna inhibition of six1 expression |
EP2283846A1 (en) | 2009-08-12 | 2011-02-16 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | miRNA compounds for treatment of prostate carcinoma |
EP2910648A1 (en) | 2009-08-24 | 2015-08-26 | National University Corporation Kanazawa University | Detection of biliary tract cancer by gene expression profiling |
DK177532B1 (en) | 2009-09-17 | 2013-09-08 | Bio Bedst Aps | Medical use of sPLA2 hydrolysable liposomes |
US20120231970A1 (en) * | 2009-09-30 | 2012-09-13 | Japan Health Sciences Foundation | Colon cancer marker and method for testing for colon cancer |
EP2504452A4 (en) | 2009-11-23 | 2014-06-11 | Univ Ohio State Res Found | SUBSTANCES AND METHODS THAT CAN BE USED TO ACT ON THE GROWTH, MIGRATION, AND INVASION OF TUMOR CELLS |
US8846631B2 (en) | 2010-01-14 | 2014-09-30 | Regulus Therapeutics Inc. | MicroRNA compositions and methods |
CN101875973B (zh) * | 2010-04-01 | 2013-01-09 | 华中农业大学 | 与猪免疫性状相关的小rna分子标记与应用 |
WO2011128886A1 (en) | 2010-04-12 | 2011-10-20 | Ramot At Tel Aviv University Ltd. | A micro-rna for cancer diagnosis, prognosis and therapy |
EP3444346B1 (en) | 2010-04-23 | 2022-07-27 | University of Massachusetts | Aav-based treatment of cholesterol-related disorders |
US9598734B2 (en) | 2010-04-29 | 2017-03-21 | Medical Prognosis Institute A/S | Methods and devices for predicting treatment efficacy |
WO2011156777A1 (en) | 2010-06-10 | 2011-12-15 | Fred Hutchinson Cancer Research Center | Use of blood mir-210 for cancer prognosis |
US20120156246A1 (en) * | 2010-06-16 | 2012-06-21 | Bamdad Cynthia C | Reprogramming cancer cells |
AU2011274619B2 (en) | 2010-07-06 | 2016-11-10 | Interna Technologies Bv | miRNA and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated BRAF pathway |
WO2012005339A1 (ja) | 2010-07-08 | 2012-01-12 | 武田薬品工業株式会社 | 糖尿病の予防・治療剤 |
JP5099570B2 (ja) | 2010-07-12 | 2012-12-19 | 国立大学法人鳥取大学 | siRNA導入による新規hiPSC作製法 |
US8980549B2 (en) | 2010-08-01 | 2015-03-17 | Ramot At Tel Aviv University Ltd. | MicroRNA patterns for the diagnosis, prognosis and treatment of melanoma |
EP2622076A1 (en) | 2010-09-30 | 2013-08-07 | University of Zürich | Treatment of b-cell lymphoma with microrna |
US8951983B2 (en) | 2010-10-17 | 2015-02-10 | Yeda Research And Development Co. Ltd. | Methods and compositions for the treatment of insulin-associated medical conditions |
AU2011326032B2 (en) | 2010-11-12 | 2016-10-06 | The Ohio State University Research Foundation | Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer |
BR112013011942A2 (pt) | 2010-11-15 | 2016-11-01 | Univ Michigan | formulação, forma de dosagem de droga para administração transmucosa oral, sistema transmucoso de fornecimento de droga, método de tratamento e profilaxia de uma doença ou distúrbio, método de tratamento, formulação, método para tratamento ou prevenção de carcinoma de célula escamosa de cabeça e pescoço (hnscc), método para quimioprevenção de um câncer oral ou condição pré-cancerosa, método para aumentar a concentração de uma composição de retinida, método de tratamento e profilaxia de uma doença ou condição, método de ratamento de um sujeito apresentando uma condição médica sintomática, método de tratamento de um câncer oral ou condição pré-cancerosa num paciente, método para fazer um sistema de fornecimento de droga bucal, método para aumentar a liberação e permeação de uma composição de retinida. |
EP2942403B1 (en) * | 2010-12-01 | 2017-04-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for predicting the outcome of a cancer by analysing mirna expression |
EP2474617A1 (en) | 2011-01-11 | 2012-07-11 | InteRNA Technologies BV | Mir for treating neo-angiogenesis |
CN103703142A (zh) | 2011-01-26 | 2014-04-02 | 西菲伊德公司 | 检测肺癌的方法 |
WO2012106591A1 (en) | 2011-02-03 | 2012-08-09 | Mirna Therapeutics, Inc. | Synthetic mimics of mir-34 |
CN103459598B (zh) | 2011-02-03 | 2016-08-10 | 米尔纳医疗股份有限公司 | Mir-124的合成模拟物 |
RS59161B1 (sr) * | 2011-02-07 | 2019-10-31 | Gabriella Sozzi | Mikro-rnk biomarkeri za identifikovanje rizika i/ili dijagnostikovanje tumora pluća |
JP2014509852A (ja) * | 2011-03-07 | 2014-04-24 | ジ・オハイオ・ステート・ユニバーシティ | マイクロRNA−155(miR−155)により誘導される変異誘発活性は炎症および癌を結び付ける |
JP2014515024A (ja) | 2011-04-12 | 2014-06-26 | ベス イスラエル デアコネス メディカル センター, インコーポレイテッド | マイクロrna阻害剤および疾患におけるその使用 |
RU2626540C2 (ru) * | 2011-04-18 | 2017-07-28 | Диамир, Ллс | Способы обнаружения патологических изменений в органе или системе органов |
EP3318634A1 (en) | 2011-04-21 | 2018-05-09 | University of Massachusetts | Raav-based compositions and methods for treating diseases involving dominant-negative or gain of function mutations |
WO2012174293A2 (en) | 2011-06-14 | 2012-12-20 | Nestec Sa | Methods for identifying inflammatory bowel disease patients with dysplasia or cancer |
US9644241B2 (en) | 2011-09-13 | 2017-05-09 | Interpace Diagnostics, Llc | Methods and compositions involving miR-135B for distinguishing pancreatic cancer from benign pancreatic disease |
US20150024389A1 (en) | 2011-09-16 | 2015-01-22 | Lsip, Llc | Method for detecting bladder cancer cells, primer used in method for detecting bladder cancer cells, and bladder cancer marker |
JP2014530612A (ja) | 2011-10-14 | 2014-11-20 | ジ・オハイオ・ステート・ユニバーシティ | 卵巣がんに関する方法および材料 |
WO2013067048A1 (en) * | 2011-10-31 | 2013-05-10 | The Ohio State University | Materials and methods related to mir-221 and hepatocellular carcinoma |
AU2012347498A1 (en) * | 2011-12-10 | 2014-06-26 | Ohio State Innovation Foundation | MiRNAs useful to reduce lung cancer tumorigenesis and chemotherapy resistance and related compositons and methods |
CN104619353A (zh) * | 2011-12-13 | 2015-05-13 | 俄亥俄州国家创新基金会 | 与miR-21和miR-29a相关的方法和组合物、外切体抑制和癌症转移 |
US9850541B2 (en) * | 2011-12-19 | 2017-12-26 | Valley Health System | Methods and kits for detecting subjects at risk of having cancer |
WO2013103889A1 (en) | 2012-01-06 | 2013-07-11 | Viomics, Inc. | System and method of detecting rnas altered by cancer in peripheral blood |
JP2015511121A (ja) * | 2012-01-20 | 2015-04-16 | ジ・オハイオ・ステート・ユニバーシティ | 浸潤性および予後に関する乳がんバイオマーカーシグネチャー |
WO2014012047A1 (en) * | 2012-07-12 | 2014-01-16 | University Of Louisville Research Foundation, Inc. | Systems and methods for diagnosis, prognosis, and treatment of cancer |
DK3435084T3 (da) | 2012-08-16 | 2023-05-30 | Mayo Found Medical Education & Res | Prostatakræftprognose under anvendelse af biomarkører |
CN102816862A (zh) * | 2012-09-19 | 2012-12-12 | 南开大学 | miRNA 222在前列腺癌血清学诊断试剂盒中的应用 |
EP2711430A1 (en) * | 2012-09-24 | 2014-03-26 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | MicroRNA based method for diagnosis of colorectal tumors and of metastasis |
US20150307542A1 (en) | 2012-10-03 | 2015-10-29 | Moderna Therapeutics, Inc. | Modified nucleic acid molecules and uses thereof |
IN2015DN04209A (zh) * | 2012-10-18 | 2015-10-16 | Univ Western Australia | |
EP2909324B1 (en) | 2012-10-25 | 2020-02-26 | Tocagen Inc. | Retroviral vector with mini-promoter cassette |
DK2922554T3 (en) | 2012-11-26 | 2022-05-23 | Modernatx Inc | Terminalt modificeret rna |
EP2746406B1 (en) | 2012-12-18 | 2017-08-23 | Samsung Electronics Co., Ltd. | Composition and kit for diagnosing breast cancer including miRNAs within vesicle, and method of diagnosing breast cancer using the same |
EP2946014A2 (en) | 2013-01-17 | 2015-11-25 | Moderna Therapeutics, Inc. | Signal-sensor polynucleotides for the alteration of cellular phenotypes |
WO2014152646A1 (en) * | 2013-03-14 | 2014-09-25 | The Trustees Of Princeton University | Micrornas as functional mediators and biomarkers of bone metastasis |
CA2907377A1 (en) | 2013-03-15 | 2014-09-18 | Baylor Research Institute | Tissue and blood-based mirna biomarkers for the diagnosis, prognosis and metastasis-predictive potential in colorectal cancer |
KR20150043937A (ko) | 2013-10-15 | 2015-04-23 | 삼성전자주식회사 | 개체의 간암 진단용 조성물, 개체의 간암 진단하는 방법 및 개체의 간암 진단에 필요한 정보를 얻는 방법 |
KR101685107B1 (ko) * | 2013-10-16 | 2016-12-09 | 서울대학교산학협력단 | 개체의 조직 또는 장기 손상 진단용 조성물 및 키트, 개체의 조직 또는 장기 손상을 예측 또는 진단하는 방법 및 치료제를 탐색하는 방법 |
US10632349B2 (en) | 2017-11-03 | 2020-04-28 | Parsons Xtreme Golf, LLC | Golf club heads and methods to manufacture golf club heads |
WO2015153679A1 (en) * | 2014-03-31 | 2015-10-08 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Microrna assay for detection and management of pancreatic cancer precursors |
US9631194B2 (en) | 2014-04-04 | 2017-04-25 | Beth Israel Deaconess Medical Center | Methods and compositions for use in treatment of FOXP2-related cancers |
CN103937888B (zh) * | 2014-04-14 | 2016-08-17 | 上海交通大学 | 鉴别胃癌的血浆microRNA标志物的筛选与应用 |
CA2946309C (en) * | 2014-04-25 | 2021-11-09 | Michael MILSOM | Synthetic bcl11a micrornas for treating hemoglobinopathies |
EP3409794B1 (en) * | 2014-05-02 | 2021-03-24 | Ruprecht-Karls-Universität Heidelberg | Circulating mirnas as early detection marker and prognostic marker |
CN111996254A (zh) | 2014-06-12 | 2020-11-27 | 东丽株式会社 | 前列腺癌的检测试剂盒或装置以及检测方法 |
ES2481819B1 (es) * | 2014-06-12 | 2015-04-01 | Sistemas Genómicos, S.L. | Método de evaluación para evaluar una posibilidad de cáncer de mama |
CN113151468A (zh) * | 2014-06-13 | 2021-07-23 | 东丽株式会社 | 乳癌的检测试剂盒或装置以及检测方法 |
KR102633955B1 (ko) | 2014-06-13 | 2024-02-06 | 도레이 카부시키가이샤 | 대장암의 검출 키트 또는 디바이스 및 검출 방법 |
KR102585737B1 (ko) | 2014-06-16 | 2023-10-10 | 국립연구개발법인 고쿠리츠간켄큐센터 | 위암의 검출 키트 또는 디바이스 및 검출 방법 |
JP5795115B1 (ja) * | 2014-06-19 | 2015-10-14 | アイリスオーヤマ株式会社 | Led照明装置 |
US9623040B2 (en) | 2014-07-14 | 2017-04-18 | The Board Of Trustees Of The Leland Stanford Junior University | Immunomodulation by controlling expression levels of microRNAs in dendritic cells |
EP4137586A1 (en) * | 2014-08-07 | 2023-02-22 | Agency for Science, Technology and Research | Microrna biomarker for the diagnosis of gastric cancer |
CN104293923A (zh) * | 2014-09-19 | 2015-01-21 | 浙江大学 | 荧光定量PCR检测组织中miR-100含量的试剂盒及其应用 |
EP3198035B1 (en) | 2014-09-26 | 2022-11-02 | Allarity Therapeutics Europe ApS | Methods for predicting drug responsiveness |
US10711270B2 (en) | 2014-10-03 | 2020-07-14 | University Of Massachusetts | High efficiency library-identified AAV vectors |
WO2016054554A1 (en) | 2014-10-03 | 2016-04-07 | University Of Massachusetts | Heterologous targeting peptide grafted aavs |
AU2015335923B2 (en) | 2014-10-21 | 2021-04-29 | University Of Massachusetts | Recombinant AAV variants and uses thereof |
EP3041948B1 (en) | 2014-11-10 | 2019-01-09 | Modernatx, Inc. | Alternative nucleic acid molecules containing reduced uracil content and uses thereof |
CN104491880A (zh) * | 2014-12-31 | 2015-04-08 | 中国人民解放军第三军医大学 | MicroRNA-141作为抑制剂的用途 |
US10584321B2 (en) | 2015-02-13 | 2020-03-10 | University Of Massachusetts | Compositions and methods for transient delivery of nucleases |
WO2016138287A1 (en) * | 2015-02-25 | 2016-09-01 | Washington University | METHODS TO DETECT MOTOR NEURON DISEASE COMPRISING MICRO-RNAs |
JP6548184B2 (ja) * | 2015-02-27 | 2019-07-24 | 国立大学法人北海道大学 | がんの悪性度、予後及び/又は抗がん剤治療の有効性を判定するためのバイオマーカー、抗がん剤を選択するためのコンパニオン診断薬並びに抗がん剤 |
CA3021949C (en) | 2015-04-24 | 2023-10-17 | University Of Massachusetts | Modified aav constructs and uses thereof |
CN107921147B (zh) * | 2015-05-05 | 2021-12-24 | 江苏命码生物科技有限公司 | 一种新的前体miRNA及其在肿瘤治疗中的应用 |
CN108138180A (zh) | 2015-06-05 | 2018-06-08 | 米拉根医疗股份有限公司 | 用于治疗皮肤t细胞淋巴瘤(ctcl)的mir-155抑制剂 |
US11426469B2 (en) | 2015-10-22 | 2022-08-30 | University Of Massachusetts | Prostate-targeting adeno-associated virus serotype vectors |
US11253576B2 (en) | 2015-10-22 | 2022-02-22 | University Of Massachusetts | Methods and compositions for treating metabolic imbalance in neurodegenerative disease |
KR102601499B1 (ko) * | 2015-11-06 | 2023-11-13 | 연세대학교 산학협력단 | miRNA 발현 수준으로부터 UQCRB 관련 질병을 진단하는 방법 |
WO2017102841A1 (en) * | 2015-12-15 | 2017-06-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing or prognosing prostate cancer |
US20210206818A1 (en) | 2016-01-22 | 2021-07-08 | Modernatx, Inc. | Messenger ribonucleic acids for the production of intracellular binding polypeptides and methods of use thereof |
WO2017136536A1 (en) | 2016-02-02 | 2017-08-10 | University Of Massachusetts | Method to enhance the efficiency of systemic aav gene delivery to the central nervous system |
EP3413928B1 (en) | 2016-02-12 | 2022-04-20 | University of Massachusetts | Anti-angiogenic mirna therapeutics for inhibiting corneal neovascularization |
JP6670119B2 (ja) | 2016-02-15 | 2020-03-18 | Kyb株式会社 | ベーンポンプ |
US10767178B2 (en) * | 2016-02-26 | 2020-09-08 | Yale University | Compositions and methods of using piRNAS in cancer diagnostics and therapeutics |
EP3426781A2 (en) | 2016-03-07 | 2019-01-16 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Micrornas and methods of their use |
CN105755123A (zh) * | 2016-03-21 | 2016-07-13 | 河北医科大学第医院 | 一种结直肠癌相关的标志物、其引物及应用 |
WO2017176929A1 (en) | 2016-04-05 | 2017-10-12 | University Of Massachusetts | Compositions and methods for selective inhibition of grainyhead-like protein expression |
US11446398B2 (en) | 2016-04-11 | 2022-09-20 | Obsidian Therapeutics, Inc. | Regulated biocircuit systems |
US11413356B2 (en) | 2016-04-15 | 2022-08-16 | University Of Massachusetts | Methods and compositions for treating metabolic imbalance |
ES2941411T3 (es) | 2016-05-18 | 2023-05-22 | Modernatx Inc | Polinucleótidos que codifican interleucina-12 (IL12) y usos de los mismos |
US10202604B2 (en) * | 2016-05-26 | 2019-02-12 | Stemirna Therapeutics Co., Ltd. | Methods of using microRNA-141 |
JP2019525901A (ja) | 2016-06-14 | 2019-09-12 | モデルナティエックス インコーポレイテッドModernaTX,Inc. | 脂質ナノ粒子の安定化製剤 |
WO2017218852A1 (en) | 2016-06-15 | 2017-12-21 | University Of Massachusetts | Recombinant adeno-associated viruses for delivering gene editing molecules to embryonic cells |
CA3029119A1 (en) | 2016-06-29 | 2018-01-04 | Crispr Therapeutics Ag | Materials and methods for treatment of friedreich ataxia and other related disorders |
EP3478829A1 (en) | 2016-06-29 | 2019-05-08 | Crispr Therapeutics AG | Materials and methods for treatment of myotonic dystrophy type 1 (dm1) and other related disorders |
WO2018002762A1 (en) | 2016-06-29 | 2018-01-04 | Crispr Therapeutics Ag | Materials and methods for treatment of amyotrophic lateral sclerosis (als) and other related disorders |
EP3481857A1 (en) | 2016-07-06 | 2019-05-15 | Crispr Therapeutics AG | Materials and methods for treatment of pain related disorders |
AU2017292169B2 (en) | 2016-07-06 | 2021-12-23 | Vertex Pharmaceuticals Incorporated | Materials and methods for treatment of pain related disorders |
US10801025B2 (en) | 2016-07-26 | 2020-10-13 | Indiana University Research And Technology Corporation | MicroRNA therapy for pancreatic cancer |
CN106244679B (zh) * | 2016-07-27 | 2019-11-22 | 中国医学科学院基础医学研究所 | miR-100抑制剂在降低癌症转移中的用途 |
CN106237344A (zh) * | 2016-08-04 | 2016-12-21 | 北京信生元生物医学科技有限公司 | miR‑1255在制备治疗膀胱癌药物中的应用 |
WO2018039490A1 (en) | 2016-08-24 | 2018-03-01 | Genomedx Biosciences, Inc. | Use of genomic signatures to predict responsiveness of patients with prostate cancer to post-operative radiation therapy |
US10457940B2 (en) | 2016-09-22 | 2019-10-29 | University Of Massachusetts | AAV treatment of Huntington's disease |
CN106381298A (zh) * | 2016-09-27 | 2017-02-08 | 和泓(厦门)生物技术有限公司 | 一种rna抑制剂及其应用 |
US9725769B1 (en) | 2016-10-07 | 2017-08-08 | Oncology Venture ApS | Methods for predicting drug responsiveness in cancer patients |
CA3040483A1 (en) | 2016-10-13 | 2018-04-19 | University Of Massachusetts | Aav capsid designs |
BR112019008369A2 (pt) | 2016-10-26 | 2019-10-01 | Modernatx Inc | ácidos ribonucleicos mensageiros para intensificar respostas imunes e métodos para uso dos mesmos |
AU2017353907B2 (en) | 2016-11-01 | 2023-11-30 | The Research Foundation For The State University Of New York | 5-halouracil-modified microRNAs and their use in the treatment of cancer |
EP3538067A1 (en) | 2016-11-08 | 2019-09-18 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
AU2017258901A1 (en) | 2016-12-30 | 2018-07-19 | Allarity Therapeutics Europe ApS | Methods for predicting drug responsiveness in cancer patients |
EP3571322B9 (en) | 2017-01-20 | 2023-10-04 | VERACYTE SD, Inc. | Molecular subtyping, prognosis, and treatment of bladder cancer |
BR112019015797A2 (pt) | 2017-02-01 | 2020-03-17 | Modernatx, Inc. | Composições de mrna terapêuticas imunomoduladoras que codificam peptídeos de mutação de oncogene de ativação |
CN110662838B (zh) | 2017-02-22 | 2024-05-28 | 克里斯珀医疗股份公司 | 用于基因编辑的组合物和方法 |
US20200040061A1 (en) | 2017-02-22 | 2020-02-06 | Crispr Therapeutics Ag | Materials and methods for treatment of early onset parkinson's disease (park1) and other synuclein, alpha (snca) gene related conditions or disorders |
EP3585899A1 (en) | 2017-02-22 | 2020-01-01 | CRISPR Therapeutics AG | Materials and methods for treatment of primary hyperoxaluria type 1 (ph1) and other alanine-glyoxylate aminotransferase (agxt) gene related conditions or disorders |
WO2018154439A1 (en) | 2017-02-22 | 2018-08-30 | Crispr Therapeutics Ag | Materials and methods for treatment of spinocerebellar ataxia type 1 (sca1) and other spinocerebellar ataxia type 1 protein (atxn1) gene related conditions or disorders |
EP3585900B1 (en) | 2017-02-22 | 2022-12-21 | CRISPR Therapeutics AG | Materials and methods for treatment of spinocerebellar ataxia type 2 (sca2) and other spinocerebellar ataxia type 2 protein (atxn2) gene related conditions or disorders |
CA3055925A1 (en) | 2017-03-09 | 2018-09-13 | Decipher Biosciences, Inc. | Subtyping prostate cancer to predict response to hormone therapy |
CA3062716A1 (en) | 2017-05-12 | 2018-11-15 | Decipher Biosciences, Inc. | Genetic signatures to predict prostate cancer metastasis and identify tumor agressiveness |
WO2018231990A2 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase |
WO2019000015A1 (en) * | 2017-06-29 | 2019-01-03 | The University Of Sydney | SIGNATURES OF MICRO-RNA WITHOUT DEATH CELLS OF BETA ISLANDS BETA CELLS |
MX2020002348A (es) | 2017-08-31 | 2020-10-08 | Modernatx Inc | Métodos de elaboración de nanopartículas lipídicas. |
EP3714055A1 (en) | 2017-11-21 | 2020-09-30 | CRISPR Therapeutics AG | Materials and methods for treatment of autosomal dominant retinitis pigmentosa |
EP3725896A4 (en) * | 2017-12-13 | 2022-01-12 | Hiroshima University | METHODS TO AID THE DETECTION OF BREAST CANCER |
CN111836892A (zh) | 2017-12-21 | 2020-10-27 | 克里斯珀医疗股份公司 | 用于治疗2a型乌谢尔综合征的材料和方法 |
WO2019123430A1 (en) | 2017-12-21 | 2019-06-27 | Casebia Therapeutics Llp | Materials and methods for treatment of usher syndrome type 2a and/or non-syndromic autosomal recessive retinitis pigmentosa (arrp) |
CN107881239B (zh) * | 2017-12-27 | 2021-04-13 | 广西壮族自治区肿瘤防治研究所 | 血浆中与结直肠癌转移相关的miRNA标志物及其应用 |
CA3089117A1 (en) | 2018-01-30 | 2019-08-08 | Modernatx, Inc. | Compositions and methods for delivery of agents to immune cells |
US20210163928A1 (en) | 2018-04-11 | 2021-06-03 | Modernatx, Inc. | Messenger rna comprising functional rna elements |
US20210071180A1 (en) * | 2018-04-23 | 2021-03-11 | Board Of Regents, The Universy Of Texas System | Microrna 584-5p compositions and methods for treating cancer |
US20220403001A1 (en) | 2018-06-12 | 2022-12-22 | Obsidian Therapeutics, Inc. | Pde5 derived regulatory constructs and methods of use in immunotherapy |
US11535899B2 (en) | 2018-08-10 | 2022-12-27 | Toray Industries, Inc. | Kit, device and method for detecting prostate cancer |
EP3852728A1 (en) | 2018-09-20 | 2021-07-28 | Modernatx, Inc. | Preparation of lipid nanoparticles and methods of administration thereof |
US20210386788A1 (en) | 2018-10-24 | 2021-12-16 | Obsidian Therapeutics, Inc. | Er tunable protein regulation |
WO2020132494A2 (en) * | 2018-12-21 | 2020-06-25 | Baylor Research Institute | Methods for prognosing, diagnosing, and treating gastric cancer |
KR20210135494A (ko) | 2019-01-31 | 2021-11-15 | 모더나티엑스, 인크. | 지질 나노입자의 제조 방법 |
CN109913454B (zh) * | 2019-03-05 | 2021-08-10 | 上海珑欣生物医学科技有限公司 | 一种生物活性提高的microRNA及其应用 |
CA3132840A1 (en) | 2019-03-08 | 2020-09-17 | Obsidian Therapeutics, Inc. | Human carbonic anhydrase 2 compositions and methods for tunable regulation |
EP3965895A4 (en) * | 2019-05-08 | 2023-10-25 | Nova Southeastern University | REGULATION OF NUCLEOTIDE EXCISION REPAIR (NER) BY MICRORNA FOR THE TREATMENT OF BREAST CANCER |
US20220387628A1 (en) | 2019-06-24 | 2022-12-08 | Modernatx, Inc. | Messenger rna comprising functional rna elements and uses thereof |
EP3987027A1 (en) | 2019-06-24 | 2022-04-27 | ModernaTX, Inc. | Endonuclease-resistant messenger rna and uses thereof |
WO2021046451A1 (en) | 2019-09-06 | 2021-03-11 | Obsidian Therapeutics, Inc. | Compositions and methods for dhfr tunable protein regulation |
CN110791560B (zh) * | 2019-11-06 | 2021-09-14 | 中国医学科学院医药生物技术研究所 | 一种用于阿尔茨海默病诊断和/或治疗的miRNA标志物 |
IL294866A (en) | 2020-01-31 | 2022-09-01 | Modernatx Inc | Methods for preparing fat nanoparticles |
WO2021158476A1 (en) * | 2020-02-03 | 2021-08-12 | Rutgers, The State University Of New Jersey | Microrna-7 compositions for promoting functional recovery following spinal cord injury and methods of use thereof |
CN111349704B (zh) * | 2020-03-17 | 2020-11-24 | 河北医科大学第三医院 | 肝癌的诊断产品和治疗组合物 |
US20230132602A1 (en) | 2020-04-02 | 2023-05-04 | Mirecule, Inc. | Targeted Inhibition Using Engineered Oligonucleotides |
CN111471683B (zh) * | 2020-04-15 | 2021-09-07 | 湖南省科域生物医药科技有限公司 | miR-93-5p作为诊断和治疗胃癌标志物的应用 |
US20230407401A1 (en) * | 2020-05-29 | 2023-12-21 | National Institute Of Immunology | Dna damage dependent microrna signature for cancers, methods and uses related thereto |
CN111500739B (zh) * | 2020-06-15 | 2022-05-17 | 南通大学附属医院 | 一种用于检测鼻咽癌预后的生物标志物及其应用 |
WO2022020811A1 (en) | 2020-07-24 | 2022-01-27 | Strand Therapeutics, Inc. | Lipidnanoparticle comprising modified nucleotides |
US20230277457A1 (en) | 2020-08-06 | 2023-09-07 | Modernatx, Inc. | Methods of preparing lipid nanoparticles |
CN112138161B (zh) * | 2020-08-28 | 2022-01-14 | 中国人民解放军总医院 | 一种抑制剂的用途以及一种药物的用途 |
CN112226514B (zh) * | 2020-11-23 | 2021-08-03 | 苏州京脉生物科技有限公司 | 用于早期胃癌检测的标志物组合、试剂盒及其应用 |
CN112575088B (zh) * | 2020-12-29 | 2022-07-05 | 浙江大学医学院附属妇产科医院 | 一种血浆外泌体miRNA生物标记物及其应用 |
CA3204373A1 (en) | 2021-01-08 | 2022-07-14 | Strand Therapeutics Inc. | Expression constructs and uses thereof |
KR102548285B1 (ko) * | 2021-02-10 | 2023-06-28 | 영남대학교 산학협력단 | 특발성 신증후군 진단용 바이오마커 조성물 및 이의 용도 |
EP4334446A1 (en) | 2021-05-03 | 2024-03-13 | CureVac SE | Improved nucleic acid sequence for cell type specific expression |
CN113322237B (zh) * | 2021-06-16 | 2022-05-13 | 中国医学科学院肿瘤医院 | 一种vav2基因缺失的肿瘤细胞系 |
CN114081896B (zh) * | 2021-11-22 | 2023-03-14 | 新乡医学院 | let-7i-3p在制备治疗结直肠癌的药物中的应用及方法 |
WO2023170659A1 (en) | 2022-03-11 | 2023-09-14 | Consejo Nacional De Investigaciones Cientificas Y Tecnicas (Conicet) | Breast cancer diagnostic and treatment |
WO2023212618A1 (en) | 2022-04-26 | 2023-11-02 | Strand Therapeutics Inc. | Lipid nanoparticles comprising venezuelan equine encephalitis (vee) replicon and uses thereof |
WO2024026475A1 (en) | 2022-07-29 | 2024-02-01 | Modernatx, Inc. | Compositions for delivery to hematopoietic stem and progenitor cells (hspcs) and related uses |
WO2024026482A1 (en) | 2022-07-29 | 2024-02-01 | Modernatx, Inc. | Lipid nanoparticle compositions comprising surface lipid derivatives and related uses |
WO2024026487A1 (en) | 2022-07-29 | 2024-02-01 | Modernatx, Inc. | Lipid nanoparticle compositions comprising phospholipid derivatives and related uses |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004043387A2 (en) * | 2002-11-13 | 2004-05-27 | Thomas Jefferson University | Compositions and methods for cancer diagnosis and therapy |
WO2005078139A2 (en) * | 2004-02-09 | 2005-08-25 | Thomas Jefferson University | DIAGNOSIS AND TREATMENT OF CANCERS WITH MicroRNA LOCATED IN OR NEAR CANCER-ASSOCIATED CHROMOSOMAL FEATURES |
Family Cites Families (223)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4196265A (en) | 1977-06-15 | 1980-04-01 | The Wistar Institute | Method of producing antibodies |
US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4172124A (en) | 1978-04-28 | 1979-10-23 | The Wistar Institute | Method of producing tumor antibodies |
US4608337A (en) | 1980-11-07 | 1986-08-26 | The Wistar Institute | Human hybridomas and the production of human monoclonal antibodies by human hybridomas |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
US4701409A (en) | 1984-11-15 | 1987-10-20 | The Wistar Institute | Detection of B-cell neoplasms |
US4693975A (en) | 1984-11-20 | 1987-09-15 | The Wistar Institute | Human hybridroma fusion partner for production of human monoclonal antibodies |
US5139941A (en) | 1985-10-31 | 1992-08-18 | University Of Florida Research Foundation, Inc. | AAV transduction vectors |
US5015568A (en) | 1986-07-09 | 1991-05-14 | The Wistar Institute | Diagnostic methods for detecting lymphomas in humans |
US5202429A (en) | 1986-07-09 | 1993-04-13 | The Wistar Institute | DNA molecules having human BCL-2 gene sequences |
US4987071A (en) | 1986-12-03 | 1991-01-22 | University Patents, Inc. | RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US4920016A (en) | 1986-12-24 | 1990-04-24 | Linear Technology, Inc. | Liposomes with enhanced circulation time |
EP0341904B1 (en) | 1988-05-09 | 1995-03-29 | Temple University of the Commonwealth System of Higher Education | Method for predicting the effectiveness of antineoplastic therapy in individual patients |
US5198338A (en) | 1989-05-31 | 1993-03-30 | Temple University | Molecular probing for human t-cell leukemia and lymphoma |
US5149628A (en) | 1989-11-15 | 1992-09-22 | Temple University | Methods for detecting bcl-3 gene in human leukemias |
US5252479A (en) | 1991-11-08 | 1993-10-12 | Research Corporation Technologies, Inc. | Safe vector for gene therapy |
US6040140A (en) | 1991-12-11 | 2000-03-21 | Thomas Jefferson University | Methods for screening and treating leukemias resulting from all-1 region chromosome abnormalities |
WO1993012136A1 (en) | 1991-12-11 | 1993-06-24 | Thomas Jefferson University | Detection and treatment of acute leukemias resulting from chromosome abnormalities in the all-1 region |
US5633135A (en) | 1991-12-11 | 1997-05-27 | Thomas Jefferson University | Chimeric nucleic acids and proteins resulting from ALL-1 region chromosome abnormalities |
US5587308A (en) | 1992-06-02 | 1996-12-24 | The United States Of America As Represented By The Department Of Health & Human Services | Modified adeno-associated virus vector capable of expression from a novel promoter |
US5674682A (en) | 1992-10-29 | 1997-10-07 | Thomas Jefferson University | Nucleic acid primers for detecting micrometastasis of prostate cancer |
JPH08502889A (ja) | 1992-10-29 | 1996-04-02 | トーマス・ジェファーソン・ユニバーシティ | 前立腺癌の微小転移を検出する方法 |
US5478745A (en) | 1992-12-04 | 1995-12-26 | University Of Pittsburgh | Recombinant viral vector system |
US5985598A (en) | 1994-10-27 | 1999-11-16 | Thomas Jefferson University | TCL-1 gene and protein and related methods and compositions |
US7175995B1 (en) | 1994-10-27 | 2007-02-13 | Thomas Jefferson University | TCL-1 protein and related methods |
US5695944A (en) | 1995-05-05 | 1997-12-09 | Thomas Jefferson University | Modulation of bcl-2 phosphorylation |
US5567586A (en) | 1995-05-18 | 1996-10-22 | Thomas Jefferson University | Methods of indentifying solid tumors with chromosome abnormalities in the ALL-1 region |
US6242212B1 (en) | 1996-02-09 | 2001-06-05 | Thomas Jefferson University | Fragile histidine triad (FHIT) nucleic acids and methods of producing FHIT proteins |
US5928884A (en) | 1996-02-09 | 1999-07-27 | Croce; Carlo M. | FHIT proteins and nucleic acids and methods based thereon |
US5849902A (en) | 1996-09-26 | 1998-12-15 | Oligos Etc. Inc. | Three component chimeric antisense oligonucleotides |
WO1998035707A1 (en) * | 1997-02-18 | 1998-08-20 | Thomas Jefferson University | Compositions that bind to pancreatic cancer cells and methods of using the same |
CA2286328A1 (en) | 1997-04-04 | 1998-10-15 | The Texas A & M University System | Noninvasive detection of colonic biomarkers using fecal messenger rna |
PT1025444E (pt) | 1997-10-21 | 2005-07-29 | Cancer Rec Tech Ltd | Determinacao de anomalia do crescimento celular |
US6303323B1 (en) | 1997-10-21 | 2001-10-16 | Cancer Research Campaign Technology Limited | Detection of dysplastic or neoplastic cells using anti-MCM5 antibodies |
WO2000003685A2 (en) | 1998-07-20 | 2000-01-27 | Thomas Jefferson University | Nitrilase homologs |
WO2000005419A1 (en) | 1998-07-24 | 2000-02-03 | Yeda Research And Development Company Ltd. | Prevention of metastasis with 5-aza-2'-deoxycytidine |
AU2869300A (en) | 1999-02-05 | 2000-08-25 | Uab Research Foundation, The | Fiber receptor-independent system for the propagation of adenoviral vectors |
US7141417B1 (en) | 1999-02-25 | 2006-11-28 | Thomas Jefferson University | Compositions, kits, and methods relating to the human FEZ1 gene, a novel tumor suppressor gene |
WO2000055169A1 (en) | 1999-03-15 | 2000-09-21 | Thomas Jefferson University | TCL-1b GENE AND PROTEIN AND RELATED METHODS AND COMPOSITIONS |
WO2001007914A1 (en) | 1999-07-26 | 2001-02-01 | Childrens Hospital Los Angeles Research Institute | Fenretinide increases antibody cellular toxicity |
US7163801B2 (en) | 1999-09-01 | 2007-01-16 | The Burnham Institute | Methods for determining the prognosis for cancer patients using tucan |
US20030206958A1 (en) | 2000-12-22 | 2003-11-06 | Cattaneo Maurizio V. | Chitosan biopolymer for the topical delivery of active agents |
US6891031B2 (en) * | 2000-02-18 | 2005-05-10 | The Regents Of The University Of California | Coordinate cytokine regulatory sequences |
WO2001068666A1 (en) | 2000-03-14 | 2001-09-20 | Thomas Jefferson University | Tcl1 enhances akt kinase activity and mediates its nuclear translocation |
IL151928A0 (en) | 2000-03-30 | 2003-04-10 | Whitehead Biomedical Inst | Rna sequence-specific mediators of rna interference |
CA2406366A1 (en) | 2000-04-11 | 2001-10-18 | Thomas Jefferson University | Muir-torre-like syndrome infhit deficient mice |
WO2001087958A2 (en) | 2000-05-16 | 2001-11-22 | Thomas Jefferson University | CRYSTAL STRUCTURE OF WORM NitFhit REVEALS THAT A Nit TETRAMER BINDS TWO Fhit DIMERS |
US7060811B2 (en) | 2000-10-13 | 2006-06-13 | Board Of Regents, The University Of Texas System | WWOX: a tumor suppressor gene mutated in multiple cancers |
US20020173478A1 (en) | 2000-11-14 | 2002-11-21 | The Trustees Of The University Of Pennsylvania | Post-transcriptional gene silencing by RNAi in mammalian cells |
US20040033502A1 (en) | 2001-03-28 | 2004-02-19 | Amanda Williams | Gene expression profiles in esophageal tissue |
US20050176025A1 (en) | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of B-cell CLL/Lymphoma-2 (BCL-2) gene expression using short interfering nucleic acid (siNA) |
CA2462144C (en) | 2001-09-28 | 2016-09-20 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Micro-rna molecules |
US7371736B2 (en) | 2001-11-07 | 2008-05-13 | The Board Of Trustees Of The University Of Arkansas | Gene expression profiling based identification of DKK1 as a potential therapeutic targets for controlling bone loss |
US7455995B2 (en) | 2001-11-09 | 2008-11-25 | The Ohio State University Research Foundation | BAALC expression as a diagnostic marker for acute leukemia |
GB0128898D0 (en) | 2001-12-03 | 2002-01-23 | Biotech Res Ventures Pte Ltd | Materials and methods relating to the stabilization and activation of a tumour suppressor protein |
WO2003069853A1 (en) | 2002-02-12 | 2003-08-21 | Nokia Corporation | Method for controlling data transmission, and data transmission system |
US7790905B2 (en) | 2002-02-15 | 2010-09-07 | Mcneil-Ppc, Inc. | Pharmaceutical propylene glycol solvate compositions |
AU2003213119A1 (en) | 2002-02-20 | 2003-09-09 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF BCL2 GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
AU2003224672B2 (en) | 2002-03-08 | 2010-02-04 | Eisai R&D Management Co., Ltd. | Macrocyclic compounds useful as pharmaceuticals |
WO2003078662A1 (en) * | 2002-03-13 | 2003-09-25 | Genomic Health | Gene expression profiling in biopsied tumor tissues |
AU2003226279A1 (en) | 2002-04-08 | 2003-10-27 | Ciphergen Biosystems, Inc. | Serum biomarkers in hepatocellular carcinoma |
DE60329836D1 (de) | 2002-04-29 | 2009-12-10 | Univ Jefferson | Humane chronische lymphozytische leukämie im mausmodell durch gezielte expression von tcl1 |
JP2005536195A (ja) | 2002-05-31 | 2005-12-02 | ザ リージェント オブ ザ ユニバーシティ オブ カリフォルニア | 哺乳動物細胞における効率的なrna干渉のための方法 |
US7217568B2 (en) | 2002-05-31 | 2007-05-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of identifying and isolating stem cells and cancer stem cells |
US7148342B2 (en) | 2002-07-24 | 2006-12-12 | The Trustees Of The University Of Pennyslvania | Compositions and methods for sirna inhibition of angiogenesis |
US20050260639A1 (en) | 2002-09-30 | 2005-11-24 | Oncotherapy Science, Inc. | Method for diagnosing pancreatic cancer |
CA2501602A1 (en) | 2002-10-11 | 2004-04-22 | Thomas Jefferson University | Novel tumor suppressor gene and compositions and methods for making and using the same |
US20050266443A1 (en) | 2002-10-11 | 2005-12-01 | Thomas Jefferson University | Novel tumor suppressor gene and compositions and methods for making and using the same |
CN1719973A (zh) | 2002-11-13 | 2006-01-11 | 托马斯杰斐逊大学 | 用于癌症诊断和治疗的组合物和方法 |
US7250496B2 (en) | 2002-11-14 | 2007-07-31 | Rosetta Genomics Ltd. | Bioinformatically detectable group of novel regulatory genes and uses thereof |
US20040102421A1 (en) | 2002-11-21 | 2004-05-27 | Children's Hospital Research Center At Oakland | Tocopherol and tocotrienol anti-inflammatory medicaments |
WO2004071464A2 (en) * | 2003-02-12 | 2004-08-26 | Johns Hopkins University School Of Medicine | Diagnostic application of differentially-expressed genes in lympho-hematopoietic stem cells |
US7183384B2 (en) | 2003-03-06 | 2007-02-27 | A & G Pharmaceutical, Inc. | Monoclonal antibody 7H11 reactive with human cancer |
WO2004081196A2 (en) | 2003-03-11 | 2004-09-23 | Qlt Usa Inc. | Formulations for cell- schedule dependent anticancer agents |
US20050069918A1 (en) | 2003-05-29 | 2005-03-31 | Francois Claret | JAB1 as a prognostic marker and a therapeutic target for human cancer |
ATE420160T1 (de) | 2003-06-18 | 2009-01-15 | Genelux Corp | Modifizierte rekombinante vacciniaviren, verwendungen davon |
WO2005013901A2 (en) | 2003-07-31 | 2005-02-17 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and compositions for use in modulation of small non-coding rnas |
WO2005047505A2 (en) * | 2003-08-07 | 2005-05-26 | Whitehead Institute For Biomedical Research | Methods and products for expression of micro rnas |
US20050037362A1 (en) | 2003-08-11 | 2005-02-17 | Eppendorf Array Technologies, S.A. | Detection and quantification of siRNA on microarrays |
CA2539651A1 (en) | 2003-09-22 | 2005-04-07 | Rosetta Inpharmatics Llc | Synthetic lethal screen using rna interference |
JPWO2005028648A1 (ja) | 2003-09-22 | 2007-11-15 | 愛知県 | リンパ腫の病型および予後診断方法 |
WO2005028675A2 (en) | 2003-09-24 | 2005-03-31 | Oncotherapy Science, Inc. | Methods for detecting, diagnosing and treating hepatocellular carcinomas (hcc) |
WO2005047477A2 (en) | 2003-11-07 | 2005-05-26 | University Of Massachusetts | Interspersed repetitive element rnas as substrates, inhibitors and delivery vehicles for rnai |
US20050164252A1 (en) * | 2003-12-04 | 2005-07-28 | Yeung Wah Hin A. | Methods using non-genic sequences for the detection, modification and treatment of any disease or improvement of functions of a cell |
EP2299266A1 (en) | 2003-12-19 | 2011-03-23 | The Regents of the University of California | Methods and materials for assessing prostate cancer therapies |
JP4120002B2 (ja) | 2004-01-07 | 2008-07-16 | 愛知県 | miRNAを用いた癌の予後判定方法、癌の遺伝子治療ベクター及び癌治療用医薬組成物 |
US20050256072A1 (en) | 2004-02-09 | 2005-11-17 | University Of Massachusetts | Dual functional oligonucleotides for use in repressing mutant gene expression |
CA2556435C (en) | 2004-02-13 | 2014-08-12 | The Rockefeller University | Anti-microrna oligonucleotide molecules |
WO2005094263A2 (en) | 2004-03-23 | 2005-10-13 | Pintex Pharmaceuticals, Inc. | Methods of determining the prognosis and treatment of subjects with colon cancer |
US20060134639A1 (en) | 2004-04-06 | 2006-06-22 | Huffel Christophe V | Method for the determination of cellular transcriptional regulation |
US7365058B2 (en) | 2004-04-13 | 2008-04-29 | The Rockefeller University | MicroRNA and methods for inhibiting same |
BRPI0509979A (pt) | 2004-04-20 | 2007-10-16 | Genaco Biomedical Products Inc | método para detectar ncrna |
JP5697297B2 (ja) * | 2004-05-14 | 2015-04-08 | ロゼッタ ジノミクス リミテッド | マイクロnasおよびその使用 |
EP2290071B1 (en) * | 2004-05-28 | 2014-12-31 | Asuragen, Inc. | Methods and compositions involving microRNA |
US7635563B2 (en) | 2004-06-30 | 2009-12-22 | Massachusetts Institute Of Technology | High throughput methods relating to microRNA expression analysis |
CN101022824A (zh) | 2004-07-01 | 2007-08-22 | 匹兹堡大学联邦系统高等教育 | 免疫抑制外体 |
US20060037088A1 (en) | 2004-08-13 | 2006-02-16 | Shulin Li | Gene expression levels as predictors of chemoradiation response of cancer |
US7893034B2 (en) | 2004-09-02 | 2011-02-22 | Yale University | Regulation of oncogenes by microRNAs |
US7642348B2 (en) * | 2004-10-04 | 2010-01-05 | Rosetta Genomics Ltd | Prostate cancer-related nucleic acids |
US7592441B2 (en) | 2004-10-04 | 2009-09-22 | Rosetta Genomics Ltd | Liver cancer-related nucleic acids |
FR2877350B1 (fr) | 2004-11-03 | 2010-08-27 | Centre Nat Rech Scient | IDENTIFICATION ET UTILISATION DE miRNAs IMPLIQUES DANS LA DIFFERENCIATION DE CELLULES ISSUES D'UNE LEUCEMIE MYELOIDE |
EP2281888B1 (en) * | 2004-11-12 | 2015-01-07 | Asuragen, Inc. | Methods and compositions involving miRNA and miRNA inhibitor molecules |
EP1662259A1 (en) | 2004-11-25 | 2006-05-31 | Cellzome Ag | Use of Eph receptor inhibitors for the treatment of neurodegenerative diseases |
WO2006066158A2 (en) | 2004-12-14 | 2006-06-22 | Alnylam Pharmaceuticals, Inc. | Rnai modulation of mll-af4 and uses thereof |
US20060185027A1 (en) | 2004-12-23 | 2006-08-17 | David Bartel | Systems and methods for identifying miRNA targets and for altering miRNA and target expression |
EP1959012A3 (en) | 2004-12-29 | 2009-12-30 | Exiqon A/S | Novel oligonucleotide compositions and probe sequences useful for detection and analysis of microRNAs and their target mRNAs |
DE602006016739D1 (de) | 2005-01-25 | 2010-10-21 | Rosetta Inpharmatics Llc | Verfahren zur quantifizierung kleiner rna-moleküle |
US8071306B2 (en) | 2005-01-25 | 2011-12-06 | Merck Sharp & Dohme Corp. | Methods for quantitating small RNA molecules |
JP2008529531A (ja) | 2005-02-11 | 2008-08-07 | ウィスコンシン・アルムニ・リサーチ・ファウンデーション | Mir−155アッセイ |
CN103251946A (zh) | 2005-02-23 | 2013-08-21 | 健泰科生物技术公司 | 使用her二聚化抑制剂在癌症患者中延长病情进展前时间或存活 |
US20070065840A1 (en) | 2005-03-23 | 2007-03-22 | Irena Naguibneva | Novel oligonucleotide compositions and probe sequences useful for detection and analysis of microRNAS and their target mRNAS |
GB2425311A (en) | 2005-04-15 | 2006-10-25 | Ist Superiore Sanita | Micro RNA against kit protein |
AU2006242154B2 (en) | 2005-05-02 | 2011-11-03 | Cold Spring Harbor Laboratory | Composition and methods for cancer diagnosis utilizing the mir 17-92 cluster |
US20070065844A1 (en) | 2005-06-08 | 2007-03-22 | Massachusetts Institute Of Technology | Solution-based methods for RNA expression profiling |
US20060292616A1 (en) | 2005-06-23 | 2006-12-28 | U.S. Genomics, Inc. | Single molecule miRNA-based disease diagnostic methods |
CA2617581A1 (en) | 2005-08-01 | 2007-02-08 | The Ohio State University Research Foundation | Microrna-based methods for the diagnosis of breast cancer |
US20070213292A1 (en) | 2005-08-10 | 2007-09-13 | The Rockefeller University | Chemically modified oligonucleotides for use in modulating micro RNA and uses thereof |
CA2618995A1 (en) | 2005-08-10 | 2007-02-22 | The Rockefeller University | Antagomirs for use in inhibiting mir-122 |
ES2523989T3 (es) | 2005-09-12 | 2014-12-03 | The Ohio State University Research Foundation | Composiciones para la terapia de cánceres asociados con BCL2 |
WO2007031091A2 (en) | 2005-09-15 | 2007-03-22 | Santaris Pharma A/S | Rna antagonist compounds for the modulation of p21 ras expression |
CA2624531A1 (en) | 2005-10-05 | 2007-04-19 | Carlo M. Croce | Wwox gene, vectors containing the same, and uses in treatment of cancer |
US20070092882A1 (en) | 2005-10-21 | 2007-04-26 | Hui Wang | Analysis of microRNA |
US8445198B2 (en) | 2005-12-01 | 2013-05-21 | Medical Prognosis Institute | Methods, kits and devices for identifying biomarkers of treatment response and use thereof to predict treatment efficacy |
US7390792B2 (en) | 2005-12-15 | 2008-06-24 | Board Of Regents, The University Of Texas System | MicroRNA1 therapies |
US20100286044A1 (en) | 2005-12-29 | 2010-11-11 | Exiqon A/S | Detection of tissue origin of cancer |
EP1968622B1 (en) | 2006-01-05 | 2014-08-27 | The Ohio State University Research Foundation | Microrna expression abnormalities in pancreatic endocrine and acinar tumors |
ES2461189T3 (es) | 2006-01-05 | 2014-05-19 | The Ohio State University Research Foundation | Métodos basados en microARN y composiciones para el diagnóstico y el tratamiento de cánceres sólidos de mama o pulmón |
CN102943108B (zh) | 2006-01-05 | 2014-05-21 | 俄亥俄州立大学研究基金会 | 用于肺癌的诊断、预后和治疗的基于微小rna的方法和组合物 |
EP2369012A1 (en) | 2006-03-20 | 2011-09-28 | The Ohio State University Research Foundation | Micro-RNA fingerprints during human megakaryocytopoiesis |
WO2007112097A2 (en) | 2006-03-24 | 2007-10-04 | Children's Medical Center Corporation | Novel signature self renewal gene expression programs |
US8709379B2 (en) | 2006-03-29 | 2014-04-29 | Scitech Development, Llc | Liposomal nanoparticles and other formulations of fenretinide for use in therapy and drug delivery |
CA3042781C (en) | 2006-04-03 | 2021-10-19 | Roche Innovation Center Copenhagen A/S | Pharmaceutical composition comprising anti-mirna antisense oligonucleotides |
EP2023944A4 (en) | 2006-04-24 | 2011-10-05 | Univ Ohio State Res Found | PRE-B CELL PROLIEFERATION AND LYMPHOBLASTIC LEUKEMIA / HIGH GRADE LYMPHOMA IN MIR155 TRANSGENIC MICE |
WO2008002672A2 (en) | 2006-06-28 | 2008-01-03 | The Cleveland Clinic Foundation | Targets for use in diagnosis, prognosis and therapy of cancer |
DK2038432T3 (en) | 2006-06-30 | 2017-04-03 | Rosetta Genomics Ltd | METHOD OF DETECTING AND QUANTIFYING A TARGET NUCLEIC ACID GENERATED BY RT-PCR BY MIRNA |
ES2425387T3 (es) | 2006-07-13 | 2013-10-15 | The Ohio State University Research Foundation | Mir-106a para diagnosticar adenocarcinoma de colon de pronóstico de supervivencia pobre |
SG174107A1 (en) | 2006-08-30 | 2011-09-29 | Univ Michigan | New small molecule inhibitors of mdm2 and the uses thereof |
US20080193943A1 (en) | 2006-09-05 | 2008-08-14 | Abbott Laboratories | Companion diagnostic assays for cancer therapy |
WO2008097277A2 (en) | 2006-09-19 | 2008-08-14 | The Ohio State University Research Foundation | Tcl1 expression in chronic lymphocytic leukemia (cll) regulated by mir-29 and mir-181 |
EP2145001A2 (en) | 2006-09-19 | 2010-01-20 | Asuragen, Inc. | Mir-15, mir-26, mir -31,mir -145, mir-147, mir-188, mir-215, mir-216 mir-331, mmu-mir-292-3p regulated genes and pathways as targets for therapeutic intervention |
AU2007299828C1 (en) | 2006-09-19 | 2014-07-17 | Interpace Diagnostics, Llc | MicroRNAs differentially expressed in pancreatic diseases and uses thereof |
AU2007299804A1 (en) | 2006-09-19 | 2008-03-27 | Asuragen, Inc. | MiR-200 regulated genes and pathways as targets for therapeutic intervention |
JP2008086201A (ja) | 2006-09-29 | 2008-04-17 | Gifu Prefecture Kenkyu Kaihatsu Zaidan | マイクロrna生成の検出方法と癌の診断・治療およびマイクロrna生成調整剤 |
WO2008070301A2 (en) | 2006-10-20 | 2008-06-12 | Washington University In St. Louis | Predicting lung cancer survival using gene expression |
AU2007314212B2 (en) | 2006-11-01 | 2014-05-29 | The Govt. Of The Usa As Represented By The Secretary Of The Department Of Health And Human Services | MicroRNA expression signature for predicting survival and metastases in Hepatocellular carcinoma |
CN101316935B (zh) | 2006-11-28 | 2012-02-29 | 博奥生物有限公司 | 一种用于诊断食道癌的芯片 |
US8293684B2 (en) | 2006-11-29 | 2012-10-23 | Exiqon | Locked nucleic acid reagents for labelling nucleic acids |
WO2008070082A2 (en) | 2006-12-04 | 2008-06-12 | The Johns Hopkins University | Stem-progenitor cell specific micro-ribonucleic acids and uses thereof |
GB0624302D0 (en) | 2006-12-05 | 2007-01-17 | Istituto Superiore Di Sanito | Micro RNA |
CA2671294A1 (en) | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Mir-21 regulated genes and pathways as targets for therapeutic intervention |
CN101675165A (zh) | 2006-12-08 | 2010-03-17 | 奥斯瑞根公司 | Let-7微小rna的功能和靶标 |
EP2104734A2 (en) | 2006-12-08 | 2009-09-30 | Asuragen, INC. | Mir-20 regulated genes and pathways as targets for therapeutic intervention |
WO2008073915A2 (en) | 2006-12-08 | 2008-06-19 | Asuragen, Inc. | Micrornas differentially expressed in leukemia and uses thereof |
US20090175827A1 (en) | 2006-12-29 | 2009-07-09 | Byrom Mike W | miR-16 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
US8034560B2 (en) | 2007-01-31 | 2011-10-11 | The Ohio State University Research Foundation | MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of acute myeloid leukemia (AML) |
CA2699418A1 (en) | 2007-02-27 | 2008-09-04 | Moshe Oren | Composition and methods for modulating cell proliferation and cell death |
JP5331714B2 (ja) | 2007-03-16 | 2013-10-30 | コヴァルクス・アーゲー | タンパク質複合体をターゲティングする薬物候補の直接質量分析 |
AU2008237036A1 (en) | 2007-04-10 | 2008-10-16 | Dcb-Usa Llc | Predicting post-treatment survival in cancer patients with microRNAs |
CA2685840C (en) | 2007-04-30 | 2016-12-13 | The Ohio State University Research Foundation | Methods for differentiating pancreatic cancer from normal pancreatic function and/or chronic pancreatitis |
US20090005336A1 (en) | 2007-05-08 | 2009-01-01 | Zhiguo Wang | Use of the microRNA miR-1 for the treatment, prevention, and diagnosis of cardiac conditions |
US20090232893A1 (en) | 2007-05-22 | 2009-09-17 | Bader Andreas G | miR-143 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
US20090131354A1 (en) | 2007-05-22 | 2009-05-21 | Bader Andreas G | miR-126 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION |
WO2008154098A2 (en) | 2007-06-07 | 2008-12-18 | Wisconsin Alumni Research Foundation | Reagents and methods for mirna expression analysis and identification of cancer biomarkers |
ES2527648T3 (es) | 2007-06-08 | 2015-01-28 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Métodos para determinar el subtipo de carcinoma hepatocelular |
CN101801419A (zh) | 2007-06-08 | 2010-08-11 | 米尔纳疗法公司 | 作为治疗干预的靶标的miR-34调控的基因和路径 |
CN101918424A (zh) | 2007-06-15 | 2010-12-15 | 俄亥俄州立大学研究基金会 | 用于靶向由Drosha介导的微小RNA加工的致癌ALL-1融合蛋白 |
EP2806273B1 (en) | 2007-07-25 | 2017-09-06 | University of Louisville Research Foundation, Inc. | Exosome-associated microRNA as a diagnostic marker |
CN101809169B (zh) | 2007-07-31 | 2013-07-17 | 俄亥俄州立大学研究基金会 | 通过靶向dnmt3a和dnmt3b恢复甲基化的方法 |
ES2627059T3 (es) | 2007-08-03 | 2017-07-26 | The Ohio State University Research Foundation | Regiones ultraconservadas que codifican ARNnc |
JP5770472B2 (ja) | 2007-08-22 | 2015-08-26 | ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイションThe Ohio State University Research Foundation | ヒト急性白血病におけるepha7及びerkリン酸化の調節解除を誘発するための方法及び組成物 |
US20090061424A1 (en) | 2007-08-30 | 2009-03-05 | Sigma-Aldrich Company | Universal ligation array for analyzing gene expression or genomic variations |
CN101939446B (zh) | 2007-09-06 | 2015-02-11 | 俄亥俄州立大学研究基金会 | 人类卵巢癌中的微小rna特征 |
US20090239818A1 (en) | 2007-09-07 | 2009-09-24 | Cheng Jin Q | Effective treatment of ovarian cancer using triciribine and related compounds |
ES2575868T3 (es) | 2007-09-14 | 2016-07-01 | The Ohio State University Research Foundation | Expresión de miARN en microvesículas de sangre periférica humana y sus usos |
WO2009044899A1 (ja) | 2007-10-03 | 2009-04-09 | Kyowa Hakko Kirin Co., Ltd. | 細胞の増殖を制御する核酸 |
ES2463665T3 (es) | 2007-10-04 | 2014-05-28 | Stella Aps | Tratamiento de combinación para el tratamiento de infección por virus de la hepatitis C |
AU2008310704B2 (en) | 2007-10-11 | 2014-03-20 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Methods and compositions for the diagnosis and treatment of esphageal adenocarcinomas |
WO2009055773A2 (en) | 2007-10-26 | 2009-04-30 | The Ohio State University Research Foundation | Methods for identifying fragile histidine triad (fhit) interaction and uses thereof |
WO2009058907A2 (en) | 2007-10-29 | 2009-05-07 | Isis Pharmaceuticals, Inc. | Targeting micrornas for the treatment of liver cancer |
US20090123933A1 (en) | 2007-11-12 | 2009-05-14 | Wake Forest University Health Sciences | Microrna biomarkers in lupus |
US8071562B2 (en) | 2007-12-01 | 2011-12-06 | Mirna Therapeutics, Inc. | MiR-124 regulated genes and pathways as targets for therapeutic intervention |
WO2009086156A2 (en) | 2007-12-21 | 2009-07-09 | Asuragen, Inc. | Mir-10 regulated genes and pathways as targets for therapeutic intervention |
CN101215560B (zh) | 2007-12-26 | 2010-09-29 | 暨南大学 | 一种具有抗白血病作用的miR-21反义寡核苷酸及其应用 |
US20110053157A1 (en) | 2008-02-01 | 2011-03-03 | The General Hospital Corporation | Use of microvesicles in diagnosis, prognosis and treatment of medical diseases and conditions |
US20090263803A1 (en) | 2008-02-08 | 2009-10-22 | Sylvie Beaudenon | Mirnas differentially expressed in lymph nodes from cancer patients |
EP3112477A1 (en) | 2008-02-28 | 2017-01-04 | The Ohio State University Research Foundation | Microrna-based methods and compositions for the diagnosis, prognosis and treatment of prostate related disorders |
CA2717030A1 (en) | 2008-02-28 | 2009-09-03 | The Ohio State University Research Foundation | Microrna signatures associated with cytogenetics and prognosis in acute myeloid leukemia (aml) and uses thereof |
CA2717026A1 (en) | 2008-02-28 | 2009-09-03 | The Ohio State University Research Foundation | Microrna signatures associated with human chronic lymphocytic leukemia (ccl) and uses thereof |
CN102007223B (zh) | 2008-02-28 | 2014-06-18 | 俄亥俄州立大学研究基金会 | 用于胃癌的诊断、预后和治疗的基于微rna的方法和组合物 |
AU2009222056A1 (en) | 2008-03-01 | 2009-09-11 | Abraxis Bioscience, Llc | Treatment, diagnostic, and method for discovering antagonist using SPARC specific miRNAs |
WO2009111643A2 (en) * | 2008-03-06 | 2009-09-11 | Asuragen, Inc. | Microrna markers for recurrence of colorectal cancer |
US20090253780A1 (en) | 2008-03-26 | 2009-10-08 | Fumitaka Takeshita | COMPOSITIONS AND METHODS RELATED TO miR-16 AND THERAPY OF PROSTATE CANCER |
US20110166200A1 (en) | 2008-04-24 | 2011-07-07 | Zhan Zhang | Methods of using mir210 as a biomarker for hypoxia and as a therapeutic agent for treating cancer |
US8258111B2 (en) | 2008-05-08 | 2012-09-04 | The Johns Hopkins University | Compositions and methods related to miRNA modulation of neovascularization or angiogenesis |
WO2009147525A1 (en) | 2008-06-04 | 2009-12-10 | Karolinska Institutet Innovations Ab | Skin cancer associated micrornas |
CN102112110A (zh) | 2008-06-06 | 2011-06-29 | 米尔纳医疗股份有限公司 | 用于RNAi试剂体内递送的新型组合物 |
EP2307028B1 (en) | 2008-06-11 | 2013-10-02 | The Government of the United States of America as represented by The Secretary of the Department of Health and Human Services | Use of mir-26 family as a predictive marker of hepatocellular carcinoma and responsiveness to therapy |
US20100021734A1 (en) | 2008-07-22 | 2010-01-28 | Covalent Materials Corporation | Ceramic particles and producing method thereof |
KR101031305B1 (ko) | 2008-07-23 | 2011-04-29 | 국립암센터 | 마이크로rna-21 저해제를 포함하는 방사선 민감성증진용 조성물 |
ES2541442T3 (es) | 2008-08-01 | 2015-07-20 | Roche Innovation Center Copenhagen A/S | Modulación mediada por microARN de factores estimulantes de colonias |
AU2009281969A1 (en) | 2008-08-12 | 2010-02-18 | The Ohio State University Research Foundation | Micro-RNA-based compositions and methods for the diagnosis, prognosis and treatment of multiple myeloma |
AU2009289822B2 (en) | 2008-09-04 | 2015-04-30 | Ventana Medical Systems, Inc. | Method for prediction of the progression risk of tumors |
US20100179213A1 (en) | 2008-11-11 | 2010-07-15 | Mirna Therapeutics, Inc. | Methods and Compositions Involving miRNAs In Cancer Stem Cells |
CA2744326A1 (en) | 2008-11-21 | 2010-05-27 | The Ohio State University Research Foundation | Tcl1 as a transcriptional regulator |
JP2012510813A (ja) | 2008-12-05 | 2012-05-17 | ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション | 卵巣癌の診断および治療のためのマイクロrnaに基づく方法および組成物 |
JP2012518997A (ja) | 2009-02-26 | 2012-08-23 | ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション | 喫煙未経験者におけるマイクロrna、ならびに関連する材料および方法 |
US20110136124A1 (en) | 2009-09-23 | 2011-06-09 | Wilson Roa | Microrna expression profiles associated with lung cancer |
WO2011059776A2 (en) | 2009-10-28 | 2011-05-19 | Revision Therapeutics, Inc | Prophylaxis of skin cancer with retinamides |
US20120219958A1 (en) | 2009-11-09 | 2012-08-30 | Yale University | MicroRNA Signatures Differentiating Uterine and Ovarian Papillary Serous Tumors |
EP2504452A4 (en) | 2009-11-23 | 2014-06-11 | Univ Ohio State Res Found | SUBSTANCES AND METHODS THAT CAN BE USED TO ACT ON THE GROWTH, MIGRATION, AND INVASION OF TUMOR CELLS |
EP2354246A1 (en) | 2010-02-05 | 2011-08-10 | febit holding GmbH | miRNA in the diagnosis of ovarian cancer |
CN102844661B (zh) | 2010-02-11 | 2014-06-25 | 香港理工大学 | 胃癌的生物标志物及其应用 |
WO2011119553A1 (en) | 2010-03-26 | 2011-09-29 | The Ohio State University | Materials and methods related to modulation of mismatch repair and genomic stability by mir-155 |
CA2802738A1 (en) | 2010-06-24 | 2011-12-29 | The Ohio State University | Chronic lymphocytic leukemia modeled in mouse by targeted mir-29 expression |
US20130150430A1 (en) | 2010-08-04 | 2013-06-13 | The Ohio State University | Methods for Impairing the P53/HDM2 Auto-Regulatory Loop in Multiple Myeloma Development Using mIR-192, mIR-194 and mIR-215 |
AU2011326032B2 (en) | 2010-11-12 | 2016-10-06 | The Ohio State University Research Foundation | Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer |
WO2012097047A1 (en) | 2011-01-11 | 2012-07-19 | The Ohio State University Research Foundation | Methods to identify chronic lymphocytic leukemia disease progression |
JP2014509852A (ja) | 2011-03-07 | 2014-04-24 | ジ・オハイオ・ステート・ユニバーシティ | マイクロRNA−155(miR−155)により誘導される変異誘発活性は炎症および癌を結び付ける |
JP2014530612A (ja) | 2011-10-14 | 2014-11-20 | ジ・オハイオ・ステート・ユニバーシティ | 卵巣がんに関する方法および材料 |
JP2015511121A (ja) | 2012-01-20 | 2015-04-16 | ジ・オハイオ・ステート・ユニバーシティ | 浸潤性および予後に関する乳がんバイオマーカーシグネチャー |
US20130236453A1 (en) | 2012-03-12 | 2013-09-12 | The Ohio State University | Methods and Compositions for Modulating Acute Graft-versus-Host Disease using miR-155 Specific Inhibitors |
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- 2007-01-03 ES ES12154345T patent/ES2461189T3/es active Active
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- 2012-02-28 US US13/406,615 patent/US8658362B2/en not_active Expired - Fee Related
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-
2015
- 2015-07-15 JP JP2015141189A patent/JP2016025853A/ja active Pending
-
2016
- 2016-03-15 US US15/070,644 patent/US20160186177A1/en not_active Abandoned
- 2016-04-11 US US15/095,382 patent/US20160215352A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004043387A2 (en) * | 2002-11-13 | 2004-05-27 | Thomas Jefferson University | Compositions and methods for cancer diagnosis and therapy |
US20040152112A1 (en) * | 2002-11-13 | 2004-08-05 | Thomas Jefferson University | Compositions and methods for cancer diagnosis and therapy |
WO2005078139A2 (en) * | 2004-02-09 | 2005-08-25 | Thomas Jefferson University | DIAGNOSIS AND TREATMENT OF CANCERS WITH MicroRNA LOCATED IN OR NEAR CANCER-ASSOCIATED CHROMOSOMAL FEATURES |
Cited By (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9388470B2 (en) | 2008-12-15 | 2016-07-12 | Micromedmark Biotech Co., Ltd. | Serum or plasma microRNA as biomarkers for non-small cell lung cancer |
US10774386B2 (en) | 2008-12-15 | 2020-09-15 | Micromedmark Biotech Co., Ltd. | Serum or plasma microRNA as biomarkers for non-small cell lung cancer |
CN101988061A (zh) * | 2009-07-30 | 2011-03-23 | 江苏命码生物科技有限公司 | 乳腺癌检测标记物及其检测方法、试剂盒和生物芯片 |
CN102770561A (zh) * | 2009-12-24 | 2012-11-07 | 复旦大学 | 用于诊断不同亚型肺癌的基于组织的微-rna方法 |
US9637793B2 (en) | 2009-12-24 | 2017-05-02 | Micromedmark Biotech Co., Ltd. | Pancreatic cancer markers, and detecting methods, kits, biochips thereof |
WO2011076144A1 (en) * | 2009-12-24 | 2011-06-30 | Fudan University | Compositions and methods for microrna expession profiling in plasma of lung cancer |
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WO2011075873A1 (zh) * | 2009-12-24 | 2011-06-30 | 北京命码生科科技有限公司 | 胰腺癌标记物及其检测方法、试剂盒和生物芯片 |
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