CN105726559B - miRNA-17-3p和miRNA-19b-1组合物及其应用 - Google Patents
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Abstract
本发明属于生物技术和医学领域，具体涉及一种miRNA‑17‑3p和miRNA‑19b‑1组合物及其应用。本发明提供了微小RNA miR‑17‑3p或其前体和miR‑19b‑1或其前体的组合物在制备预防或治疗肿瘤的药物中的应用。本发明首次揭示了miR‑17‑3p和miR‑19b‑1可特异性地抑制肿瘤血管生成，并且在实体瘤尤其是乳腺癌中表达显著低于正常组织；此外，本发明的miR‑17‑3p和miR‑19b‑1组合物在体外、体内均能够抑制癌细胞的生长。本发明的miR‑17‑3p和miR‑19b‑1组合物可用于制备预防或治疗实体瘤的药物，尤其是用于制备预防或治疗乳腺癌的药物。
Description
技术领域
本发明属于生物技术和医学领域，具体涉及一系列RNA小分子——miR-17-3p和miR-19b-1的组合物及其在制备预防或治疗肿瘤的药物中的应用，miR-17-3p和miR-19b-1在肿瘤血管调控以及体内抗肿瘤活性起着重要作用。
背景技术
微小RNA(microRNA，简称miRNA)是一类非编码的、具有转录后调控功能的、序列长度约18～24nt的单链小分子RNA。最早于1993年Lee等报道了在秀丽线虫(C.elegants)体内发现的一种可调节线虫发育的RNA分子，即lin-4(Lee，R.C.等，The C.elegansheterochronic gene lin-4encodes small RNAs with antisense complementarity tolin-14.Cell.1993,75:843-854)。到2000年，相继由Reinhart等(Reinhart,B.J.等，The21-nucleotide let-7RNA regulates developmental timing in Caenorhabditiselegans.Nature.2000,403:901-906)发现不同时期表达的let-7。至目前，miRNA数据库中已收录了数百种人类miRNA序列，其中三分之二已被实验证实。miRNA来源于长度约为1000bp的长链RNA初始转录产物(Pri-miRNA)，Pri-miRNA分子在细胞核中经Drosha酶剪切形成长度约60～80nt的具有茎环结构的miRNA前体(Pre-miRNA)。Pre-miRNA转运至胞质后，被进一步加工为成熟的miRNA。miRNA在动植物细胞中通过种子序列的配对程度不同实现对目标mRNA的降解或转录抑制。miRNA在物种间具有高度的保守性、时续性和组织特异性。基于miRNA的调控机制，通过生物信息学分析发现miRNA可能直接调控上百个基因的表达，此外研究表明目前所发现的miRNA直接参与30％的基因调控，进而广泛的参与多种重要的细胞生理病理过程如细胞凋亡、增殖、分化、胚胎发育、机体能量代谢、激素分泌和造血功能以及心肌肥厚等，在肿瘤疾病中，miRNA也作为关键调控因子，参与了肿瘤细胞以及其他相关间质细胞的生化过程。已有的证据显示部分miRNA的表达紊乱或成为推动肿瘤进展的关键，或成为肿瘤恶性程度以及预后的分子标志物。
自1971年由美国Folkman医生首次提出了肿瘤血管生成的概念，至今，基于肿瘤血管生成的治疗策略的研究已经成为癌症研究的最热点之一(M.Abdelrahim,S.Konduri,R.Basha,P.A.Philip,C.H.Baker,Angiogenesis:an update and potential drugapproaches(review).Int.J.Oncol.2010.36:5-18)，而抗肿瘤血管生成的肿瘤治疗策略也显示出不同于传统抗癌疗法的优越性，如耐药性发生率极低，药物毒副作用低等。鉴于血管新生对于实体肿瘤的生长、侵袭和转移起到了十分关键的作用。miRNA在肿瘤血管调控的功能研究有助于我们更好的理解肿瘤发生发展的病理机制，进一步找到治疗肿瘤疾病相关的药物靶点，从而为这类疾病的预防或治疗提供行之有效的途径。
血管生成包括血管新生(vasculogenesis)和血管发生(angiogenesis)两种机制，而血管生成的“开关”是受到机体促血管生成因子和抑制因子共同调控，包括生长因子如血管生长因子(vascular endothelial growth factor，VEGF)、血小板衍生生长因子(platelet-derived growth factor，PDGF)、成纤维细胞生长因子(fibroblast growthfactor，FGF)等，受体酪氨酸激酶(receptor tyrosine kinases，RTK)以及一些转录因子等。正常的血管生成受到细胞因子的严格调控，在两类因子的动态平衡中保持有序和稳定，而肿瘤微环境中，血管生成相关因子异常表达，致使这一平衡被打破而导致肿瘤血管发生(M.Papetti,I.M.Herman,Mechanisms of normal and tumor-derivedangiogenesis.American Journal of Physiology-Cell Physiology.2002.282:C947-C970)。研究表明对细胞因子十分敏感的血管内皮细胞以及祖细胞正是调控这一过程的主要成员。因此针对肿瘤血管生成的研究目前主要集中于对血管内皮细胞调控机制的研究。其中参与调控最主要的细胞因子为血管内皮细胞生长因子(VEGF)和碱性成纤维细胞生长因子(bFGF)，这些分子通过生长因子受体介导活化下游的信号通路调控血管内皮细胞的增殖、迁移以及存活等，对肿瘤转移起到十分关键的作用。其他一些参与血管生成调控因子也大多与VEGF调控相关，如Dumont等发现的内皮细胞特异性的酪氨酸激酶受体Tie2，及其配体Angiopoietin-1和2(Ang-1和Ang-2)，研究显示其在体内只有当和VEGF一起作用时才表现出调控血管生成的活性，表明这些因子可能参与了细胞对VEGF的应答。又如内皮细胞和肿瘤细胞共同表达的细胞表面蛋白Neuropilin为VEGF165以及胎盘生长因子(placentalgrowth factor，PlGF)的特异性受体，能够增强VEGF与其受体VEGFR-2的相互作用。此外，研究发现其他的一些细胞因子如Erphrin/Eph、Leptin等因子也参与了调控。近年来研究人员发现还有一些细胞因子参与了抗血管生成的过程，如Roundabout homolog 4(Robo 4)以及Notch ligand Delta-like 4，这些因子可以拮抗VEGF信号来发挥其抑制作用。目前对于肿瘤的血管生成和调控机理方面的研究已经不仅仅停留在基因和蛋白质的水平，随着microRNAs(miRs)的发现和深入研究，其在肿瘤血管方面的调控作用越来越受到研究人员的重视，正如研究人员Jason Fish所提到，miRNA为血管生成研究开辟了新的通路。Giraldez等通过基因敲除的方法沉默Dicer的表达来抑制miRNA的加工过程，在体内外均可以导致血管生成相关基因表达异常，并抑制血管生成。这项研究结果首次证明了miRNA在调控血管生成中起到至关重要的作用。由此，越来越多的研究人员开始关注miRNA在血管生成中的具体调控机制。而内皮细胞表达的miRNA谱成为了研究重点，尤其是内皮细胞高表达的一些miRNA有可能成为调控血管生成的关键因子。
miR-17-3p与miR-19b-1均为本领域已知的miRNA小分子，为肿瘤相关的基因簇miR-17-92中的一员，然而，现有技术对于miR-17-3p以及miR-19b-1的研究尚未深入，而对其所具有的生物学功能以及作用机制并不完全清楚。且目前国内外尚无有关miR-17-3p和/或miR-19b-1在肿瘤血管调控以及体内抗肿瘤活性的相关文献报道。
发明内容
本发明的目的在于提供miR-17-3p和miR-19b-1的组合物及其应用。
本发明通过生物信息学分析筛选出在乳腺癌中降低表达的一系列miRNAs，其中miR-17-92基因簇中的两个成员miR-17-3p及miR-19b-1被证实可以通过靶向VEGF信号通路中的关键分子VEZF1，抑制内皮细胞的增殖、迁移和成微管能力。在本发明中首次证实miR-17-3p及miR-19b-1可以显著抑制体内乳腺癌的生长，这一分子机制与调控内皮细胞的功能相关。
本发明的第一方面，提供了miR-17-3p或其前体和miR-19b-1或其前体的组合物在制备预防或治疗肿瘤药物中的应用。
即本发明提供了microRNAs在制备预防或治疗肿瘤的药物中的应用，所述的microRNAs为miR-17-3p或其前体和miR-19b-1或其前体的组合。
本发明所述的预防或治疗肿瘤的药物，尤其是预防或治疗乳腺癌的药物，所述的抗肿瘤活性是由抑制乳腺癌诱导血管生成决定的。
进一步地，本发明还提供了上述的microRNAs在制备抑制(肿瘤)血管生成药物中的应用。
进一步地，本发明还提供了上述的microRNAs在制备抑制血管生长因子(VEZF1)表达药物中的应用。
本发明所述的miR-17-3p和miR-19b-1的具体序列如下：
miR-17-3p：5'-ACUGCAGUGAAGGCACUUGU-3'(SEQ ID NO:1)。
miR-19b-1：5'-UGUGCAAAUCCAUGCAAAACUGA-3'(SEQ ID NO:2)。
本发明所述的miR-17-3p或其前体以及miR-19b-1或其前体，可以来自被分离细胞包括人、大鼠、小鼠、犬、马、牛、兔或猴等，或者可通过人工合成的方式获得。
进一步的，所述肿瘤选自：乳腺癌(优选乳腺细胞癌)、肝癌、黑色素瘤、结肠癌、子宫颈癌、肺癌、胰腺癌、胃癌或膀胱癌。
进一步的，所述组合物是药物组合物或疫苗组合物。
在本发明的第二方面中，提供了一种miR-17-3p和miR-19b-1的组合物，所述组合物包含：
(a)有效量的微小RNA miR-17-3p或其前体；
(b)有效量的微小RNA miR-19b-1或其前体；和
(c)药学上或免疫学上可接受的载体。
进一步的，组分(a)或(b)的含量占组合物总重量的0.001～99.9wt％，优选1～95wt％，更优选5～90wt％。
进一步的，所述组合物还包含治疗或预防肿瘤的其它活性成分。
进一步的，所述治疗或预防肿瘤的其它活性成分包括：化疗剂或放疗剂。
进一步的，所述其它活性成分选自：烷化剂、抗代谢药、抗肿瘤抗生素、植物类抗癌药、激素或免疫制剂；优选：细胞有丝分裂抑制剂、喜树碱、高三尖杉酯碱、丙卡巴肼、门冬酰胺酶、顺铂、卡铂、米托蒽醌、他莫昔芬、环磷酰胺、盐酸氮芥、洛莫司汀、司莫司汀、塞替派、白消安、氮甲、苯丁酸氮芥、氟尿嘧啶、喃氟啶、优氟啶、卡莫氟、巯嘌呤、甲氨蝶呤、阿糖胞苷、环胞苷、巯鸟嘌呤、六甲蜜胺、羟基脲、丝裂霉素、阿霉素、表柔比星、博莱霉素、培莱霉素、阿伐司汀、赫赛汀、格列卫、吉西他滨、托泊替康、亮丙瑞林中的一种或几种成分的联合。
进一步的，所述细胞有丝分裂抑制剂选自：长春碱、长春新碱、长春地辛、长春瑞滨、秋水仙胺、秋水仙碱、秋水仙酰胺、鬼臼毒素、依托泊苷、替尼泊苷、紫杉醇或多西他赛。
进一步的，所述组合物的形式适于：直接裸RNA注射法、脂质体包裹RNA直接注射法、金包被RNA基因枪轰击法、繁殖缺陷细菌携带质粒RNA法或复制缺陷病毒携带目的RNA法。
进一步的，所述的miR-17-3p或其前以及miR-19b-1或其前体还包括经修饰的RNA核苷酸分子，所述的修饰基本不改变核苷酸的活性；更佳地，所述修饰可提高核苷酸的活性、稳定性或治疗效果。优选的，对核苷酸的修饰包括但不限于：甲氧基化修饰、锁核酸修饰、肽核酸修饰、硫代修饰、磷酸骨架由磷脂连接骨架代替。
在本发明的第三方面中，提供了一种预防和/或治疗肿瘤的方法，所述方法包括：给予需要预防和/或治疗的对象有效量的微小RNA miR-17-3p或其前体及miR-19b-1或其前体。
本发明的有益效果如下：
本发明人经过深入研究，首次揭示了miR-17-3p及miR-19b-1可特异性的抑制VEZF1的基因表达，从而抑制调控肿瘤血管生成的VEGF信号通路，并且通过组合方式提高了体内抑制实体瘤生长的活性，特别是乳腺癌的治疗。本发明为上述肿瘤疾病的防治提供了新的靶点。
在本发明中通过给与所述哺乳动物体内的miR-17-3p及miR-19b-1的经过修饰或非修饰的成熟链或前体组合物，以抑制体内实体瘤的血管生成，可以抑制肿瘤的生长。
与现有技术相比，本发明具有以下优点：
1)在乳腺癌细胞系中过表达miR-17-3p、miR-19b-1可以抑制乳腺癌细胞诱导血管形成的能力，阻断乳腺癌的营养供给以及转移通道，促使肿瘤进入休眠期，减少转移灶的形成。
2)特异性的针对血管内皮细胞的作用进行调控，减少了由于肿瘤细胞的基因不稳定性引起的耐药性发生。鉴于成人的体内血管内皮细胞的更替极少发生，因此提高了抗癌作用的靶向性，极大减少了现有化疗药物引起的严重的不良反应。
3)与特异性较高的大分子药物相比，如抗体药物等，由于miRNA的分子较小，现有合成技术已经较为成熟，工艺简单，有利于实际应用。
附图说明
图1为临床样本中正常乳腺组织与乳腺癌组织的miR-17-3p及miR-19b-1表达水平。
图2为在转染了miR-17-3p或/和miR-19b-1的乳腺癌细胞诱导下内皮细胞迁移情况。
图3为转染了miR-17-3p或/和miR-19b-1的内皮细胞在体内形成微血管能力情况。
图4为上调miR-17-3p或/和miR-19b-1的乳腺细胞接种小鼠14天后形成的肿瘤体积；其中，17表示上调miR-17-3p组；19表示上调miR-19b-1组；17+19表示上调miR-17-3p和miR-19b-1组。
图5为生物信息学及荧光素酶法筛选得到的miR-17-3p及miR-19b-1结合VEZF1的靶点以及Western Blotting结果验证；其中，17表示上调miR-17-3p组；19表示上调miR-19b-1组；17+19表示上调miR-17-3p和miR-19b-1组。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室指南(New York：Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1、乳腺癌临床样本中microRNA表达分析
乳腺癌临床样本中存在多种miRNAs表达变化。本实验对临床取得的组织样本(南通大学附属医院2015年-2016年2月乳腺癌手术切除样本12例)包括肿瘤组织和正常乳腺组织，利用TRIzol(由Invitrogen公司提供)进行RNA抽提(具体步骤遵照试剂说明书)。并利用定量PCR对比肿瘤组织和正常乳腺组织的miR-17-3p及miR-19b-1的表达变化。
实时荧光定量PCR：常规方法提取RNA，通过microRNA芯片(QIAGEN公司提供)进行实时荧光定量PCR检测(具体步骤遵照芯片说明书)，以双标准曲线方法定量，分析各样本的microRNA浓度，并通过溶解曲线和琼脂糖凝胶电泳确定基因扩增的特异性，共测定84个microRNA，其中能同时调控内皮细胞功能的乳腺癌相关microRNA为miR-19b-1及miR-17-3p。
结果发现肿瘤组织和正常组织相比，miR-17-3p及miR-19b-1表达显著下调(图1)，此后，在肿瘤细胞模型中进一步验证该miRNAs对内皮细胞成血管能力的影响。
此外，在临床样本中，恶性程度高的肿瘤样本中未能检测到miR-17-3p或miR-19b-1的表达，提示活检组织中的miR-17-3p或miR-19b-1水平可能作为肿瘤恶性程度的重要标志物，为尽早诊断和治疗肿瘤提供了依据和作用靶点。
实施例2miR-17-3p或/和miR-19b-1过表达抑制乳腺癌细胞诱导内皮细胞功能
miR-17-3p或/和miR-19b-1过表达的方法：用Lipofectamine 2000Reagent按说明书将miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的模拟物(miR-17-3p、miR-19b-1mimics)转染至培养的乳腺癌细胞。
肿瘤微环境准备：消化上调表达miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的乳腺癌细胞MDA-MB-231，用完全培养基重悬细胞并加入transwell下腔室，每孔加入600μL，过夜孵育。待细胞贴壁后，换新鲜培养基培养48h。
基质胶准备：将冻存于-80℃冰箱的matrigel放置4℃过夜，变成液态；取150μLMatrigel，包被Transwell上室(冰上操作)，放入37℃培养箱中，孵育1h；消化内皮细胞HUVEC，配成2×106细胞悬液，用无血清培养基洗包被Matrigel的Transwell一次；每孔加入100μL细胞悬液；将transwell小室转移到上述制备的肿瘤微环境中，于37℃培养箱孵育48h；取出用PBS洗2遍，用棉球擦去上表面细胞，中性甲醛固定10min；加入结晶紫(0.1％)染色10min，室温，PBS洗2遍，显微镜下观察拍照。计数Transwell膜上中下左右五个视野中阳性染色细胞数，比较不同肿瘤微环境对细胞迁移的影响。
结果如图2所示：与正常乳腺癌细胞相比，上调表达miR-17-3p或miR-19b-1的乳腺癌细胞的诱导内皮细胞迁移能力受到了抑制。而同时上调miR-17-3p和miR-19b-1组合物的乳腺癌细胞诱导内皮细胞迁移的能力与对照组相比，显著下降。提示miR-17-3p和miR-19b-1组合物的过表达，在细胞水平上可以显著抑制乳腺癌诱导血管生成的能力，并且两种microRNA的组合物对乳腺癌细胞的诱导能力有协同抑制的作用。
实施例3过表达miR-17-3p或/和miR-19b-1对体内血管生成的抑制作用
通过建立体内成血管模型，研究体内miR-17-3p或/和miR-19b-1过表达对内皮细胞成血管能力的影响。
miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的过表达方法同实施例2。
体内成血管模型建立：将冻存于-80℃冰箱的matrigel放置4℃过夜，变成液态；将过表达miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的HUVEC细胞消化收集，并用PBS重悬为1×107细胞悬液；将细胞悬液与500μL的含肝素的matrigel混合，皮下接种Balb/c裸鼠。7天后，取出细胞组织块，进行分析。
微血管数量分析：将细胞组织块进行蜡包埋，切片，HE染色，在显微镜下观察内皮细胞形成的微血管，对血管数量进行计数。
如图3所示，实验结果表明，相较于miR-17-3p或miR-19b-1的过表达，miR-17-3p和miR-19b-1组合物的过表达能够显著抑制内皮细胞在体内的成血管活性，并且两种microRNA的组合物对内皮细胞的成血管活性有协同抑制的作用。
实施例4体内过表达miR-17-3p或/和miR-19b-1抑制小鼠肿瘤生长
为了更好的探讨miR-17-3p及miR-19b-1的内源性功能，本工作通过动物模型体内实验，转染miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的成熟片段慢病毒载体，进而建立稳定过表达miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的乳腺癌细胞株。
动物模型建立：将培养的过表达miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物的乳腺癌细胞用0.05％胰蛋白酶消化，1000rpm离心5min，重悬于PBS，在Balb/c(6-8周)裸小鼠体侧皮下接种1×106细胞0.1mL。当肿瘤平均体积达到200mm3-300mm3，每天用游标卡尺测量肿瘤大小，计算肿瘤体积，采用公式：肿瘤体积＝长×宽2×0.52。
抑瘤效果分析：如图4所示，14天后对肿瘤体积的测量结果表明miR-17-3p、miR-19b-1，以及miR-17-3p和miR-19b-1组合物对乳腺癌的生长均有抑制作用，且两种miRNA的组合物具有协同作用，抑瘤效果明显优于miR-17-3p或miR-19b-1。
实施例5miR-17-3p或/和miR-19b-1作用靶基因的寻找和验证
生物信息学法预测microRNAs的靶基因：利用TargetScan、Bibiserve、Pictar等microRNA靶基因预测网站和软件，对大鼠的microRNA的二级结构和靶基因进行预测分析，寻找序列匹配程度高、二级结构稳定、靶序列在物种间高度保守的基因进行后续验证。
双荧光报告基因法检测microRNA的靶基因：将靶基因的3'非翻译区(Untranslated Region，UTR)中能与microRNA相互作用的序列克隆至pGL3质粒中荧光素酶的3'UTR，构建重组的荧光素酶报告基因质粒。将其与表达相应microRNA的pSuper载体按一定的比例共转293T细胞。24小时后裂解细胞，采用双荧光报告基因检测系统检测荧光素酶的表达量，从而反映microRNA在离体体系中能否调控靶基因表达。
通过生物信息学分析及荧光素酶报告基因，发现VEZF1是miR-17-3p及miR-19b-1的潜在靶基因。如图5所示，内皮细胞转染miR-17-3p、miR-19b-1的mimic后，VEZF1表达减少，且miR-17-3p和miR-19b-1组合物的VEZF1表达明显少于miR-17-3p或miR-19b-1。
本发明首次揭示了miR-17-3p和miR-19b-1可特异性地抑制肿瘤血管生成，并且在实体瘤尤其是乳腺癌中表达显著低于正常组织；此外，本发明的miR-17-3p和miR-19b-1组合物在体外、体内均能够抑制癌细胞的生长。本发明的miR-17-3p和miR-19b-1组合物可用于制备预防或治疗实体瘤的药物，尤其是用于制备预防或治疗乳腺癌的药物。本发明为以乳腺癌为代表的实体瘤的诊断和防治提供了新的靶点。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可作出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (4)
1.microRNAs在制备预防或治疗乳腺癌的药物中的应用，所述的microRNAs为miR-17-3p和miR-19b-1的组合。
2.如权利要求1所述的应用，其特征在于，所述miR-17-3p的序列如SEQID NO:1所示；所述miR-19b-1的序列如SEQID NO:2所示。
3.如权利要求1所述的应用，其特征在于，所述miR-17-3p和miR-19b-1来自：人、大鼠、小鼠、犬、马、牛、兔或猴。
4.如权利要求1所述的应用，所述的药物包含：
(a)有效量的微小RNA miR-17-3p；
(b)有效量的微小RNA miR-19b-1；和
(c)药学上或免疫学上可接受的载体。
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| "MIR-17-3P inhibits angiogenesis by downregulating flk-1 in the cell growth signal pathway";Runting Yin et al.;《Journal of Vascular Research》;20121221;第50卷;摘要和第165页右栏第3段 * |
| "Mir-17-5p Regulates Breast Cancer Cell Proliferation by Inhibiting Translation of AIB1 mRNA";Anwar Hossain et al.;《Molecular and Cellular Biology》;20061130;第26卷(第21期);摘要 * |
| "MiR-19b-1 inhibits angiogenesis by blocking cell cycle progression of endothelial cells";Runting Yin et al.;《Biochemical and Biophysical Reseach Communicaitons》;20111216;第417卷;摘要 * |
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