CN112608923A - 一种抑制ddx17相关rna表达产物的核苷酸及其应用 - Google Patents

一种抑制ddx17相关rna表达产物的核苷酸及其应用 Download PDF

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CN112608923A
CN112608923A CN202110058901.6A CN202110058901A CN112608923A CN 112608923 A CN112608923 A CN 112608923A CN 202110058901 A CN202110058901 A CN 202110058901A CN 112608923 A CN112608923 A CN 112608923A
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ddx17
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何越峰
蒋成兰
毛一竹
谭婧文
周倩
尹锦瑶
孙明军
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Shanghai Generay Biotech Co ltd
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
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Abstract

本发明公开了一种抑制DDX17相关RNA表达产物的核苷酸及其应用，其特征是：所述的核苷酸特异性的抑制DDX17基因的mRNA和相关的四个环状RNA，所述核苷酸的序列是：CGCCGAAAGAAGGAGAUUA或GGGAGAUGUUUGUCCUAAA或者GGUUGAUGAGCUACGCCGA及其互补序列。本发明核苷酸能够有效抑制A549和MDA‑MB‑231细胞中DDX17基因的mRNA和相关的四个环状RNA表达，并减少A549和MDA‑MB‑231细胞生存，与抗肿瘤药物联合可以增加抗肿瘤的效果。

Description

一种抑制DDX17相关RNA表达产物的核苷酸及其应用
技术领域
本发明属于分子生物和药物领域，具体地本发明涉及一种抑制DDX17相关RNA表达产物的核苷酸及其应用。该核苷酸可抑制DDX17mRNA，hsa_circ_0001230, hsa_circ_0063328, hsa_circ_0002211, hsa_circ_00633315 个RNA的表达，也可以与其他抗肿瘤药物联合作用。
背景技术
单链共价闭合环在1976年首次被报道为类病毒，是某些植物的病原体，1979年首次通过电子显微镜在人类HeLa细胞中检测到。高通量RNA测序和生物信息学工具的发展，科学家发现circRNA是人类转录组的一个普遍特征，在许多其他后生动物中普遍存在。最近，越来越多的研究发现了circRNAs的多种功能，包括作为蛋白质支架或miR海绵以及被翻译成多肽。
circRNAs的独特结构使其半衰期更长，对RNase R的抵抗力比线性RNAs长，这使其成为诊断生物标志物和治疗靶点的潜在候选物。大量的研究已经揭示了它们独特的表达特征和在多种疾病中的重要生物学作用，如癌症、心血管疾病、神经系统疾病和自身免疫性疾病。
DDX17以保守的基序Asp-Glu-Ala-Asp（DEAD）为特征的DEAD盒蛋白是推定的RNA解旋酶。 它们涉及许多涉及RNA二级结构改变的细胞过程，例如翻译起始，核和线粒体剪接以及核糖体和剪接体组装。 该基因编码DEAD盒蛋白，它是一种被多种RNA而非dsDNA激活的ATPase。 这种蛋白质以及由DDX5基因编码的蛋白质，彼此之间的关系比与DEAD盒家族的其他成员的关系更紧密。 由于交替剪接和使用交替翻译起始密码子，该基因可编码多种同工型。在癌症的生长中起到重要作用。
RNA干扰(RNA interference，RNAi)技术利用双链小RNA高效、特异性降解细胞内同源RNA从而沉默靶基因，从而实现干扰靶基因的功能。最近RNA干扰的药物逐步回到了历史的舞台。
发明内容
本发明的目的在于提供一种抑制DDX17相关RNA表达产物的核苷酸及其应用。
本发明的目的是这样实现的，包括合成核苷酸的序列由CGCCGAAAGAAGGAGAUUA(SEQ ID NO.1) 或GGGAGAUGUUUGUCCUAAA(SEQ ID NO.2)或者GGUUGAUGAGCUACGCCGA(SEQID NO.3)互补序列。所述核苷酸可被氟代修饰、硫代修饰、甲氧基修饰、胆固醇修饰一种或几种修饰。该核苷酸可以在制备抗肿瘤药物中的应用，例如治疗肺癌、乳腺癌。也可以和其他抗肿瘤治疗药物联合使用，例如三氧化二砷。本研究有云南省创新团队培育项目(202005AE160002)资助。
本发明（优点）：发明的核苷酸具有很好的DDX17相关RNA抑制效果，作用于特异性的靶位点，而且同时对5个相关RNA作用，作用强，特异性强、毒性低、副作用小，经过修饰后修饰半衰期长，可以与多种抗肿瘤药物合用。
附图说明
图中DDX17mRNA简称mRNA，hsa_circ_0001230简称RNA30, hsa_circ_0063328 简称RNA28, hsa_circ_0002211 简称RNA11, hsa_circ_0063331简称RNA31,加入的砷为三氧化二砷。片段1 ：CGCCGAAAGAAGGAGAUUA(SEQ ID NO.1) 或片段2：GGAGAUGUUUGUCCUAAA(SEQID NO.2)或者片段3：GUUGAUGAGCUACGCCGA(SEQ ID NO.3)。
图1三个片段在A549细胞中的沉默效率，每个组由4个孔组成。
图2三个片段在MDA-MB-231细胞中的沉默，效率每个组由4个孔组成。
图3 对照组、沉默组（三个片段）、加砷组、加砷沉默（三个片段分别加砷）比较细胞活力。A549细胞活力具体数值分别为100.00、63.55、55.11、68.41、95.12、44.22、32.01、46.32， MDA-MB-231细胞活力具体数值分别为100.00、70.12、63.02、71.52、96.45、55.34、54.31、54.12。每个组由6个孔组成。
具体实施方式
下面对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明教导所作的任何变换或替换，均属于本发明的保护范围。
实施例
本实施例中的RNA序列为：片段1 CGCCGAAAGAAGGAGAUUA(SEQ ID NO.1) 或片段2GGAGAUGUUUGUCCUAAA(SEQ ID NO.2)或者片段3GUUGAUGAGCUACGCCGA(SEQ ID NO.3)其互补序列，对照的序列为GUAUGUCGACGCGCUCAUA(SEQ ID NO.4所有的序列都是从5端到3端,上海吉玛制药技术有限公司合成核苷酸在合成过程中所有sirna序列都在末端加上dTdT。DDX17mRNA，hsa_circ_0001230, hsa_circ_0063328, hsa_circ_0002211, hsa_circ_0063331的RNA序列信息存在于UCSC数据库中。本课题受云南省创新团队培育项目(202005AE160002)支持。
将A549、 MDA-MB-231细胞培养于含有1%的双抗和10％胎牛血清的1640培养基，二氧化碳箱条件为37℃，5％CO2。以3000个细胞和4000个细胞每孔铺于96孔板内。
A549细胞采用百代公司Rfect转染试剂进行转染，MDA-MB-231细胞采用碧云天公司的转染试剂进行转染，二者均按说明书的方法进行转染，转染后大约72小时后，碧云天公司CCK8的方法检测细胞活性，通过RNA提取并荧光定量检测RNA干扰效率。
过荧光定量PCR来经常RNA干扰的效率数据使用2^-ΔΔCt表示。引物分别为：检测DDX17的引物为ACCCAGATCAACGTAGGCA(SEQ ID NO.5) TCTCTGCGCATCCTTCGAG(SEQ IDNO.6，检测RNA30 GGAGCTCACTCAAATCCCAC(SEQ ID NO.7) 和ATGCTAACTTCCCACATTTGG(SEQID NO.8), 检测RNA28 CGCTCCCCAGGATTACCA(SEQ ID NO.9) 和GAGACTTGGAAAGAGATTTGG(SEQ ID NO.10), 检测RNA11 CGCTCCCCAGGATTACCA(SEQ ID NO.9)和GTGAAAAAGACCACAAATTTGGA(SEQ ID NO.11) , 检测RNA31 GGAGCTCACTCAAATCCCAC(SEQ IDNO.7)和GTGAAAAAGACCACAAATTTGGA(SEQ ID NO.12),退火温度60度。
联合效应检测采用对照组，加砷组、沉默组、加砷沉默比较来，以对照组的细胞活力为100%。
SEQUENCE LISTING
<110> 昆明医科大学
<120> 一种抑制DDX17相关RNA表达产物的核苷酸及其应用
<130> 1
<140> 1
<141> 2020-12-20
<160> 12
<170> PatentIn version 3.3
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<212> RNA
<213> 人工序列(Artificial sequence)
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cgccgaaaga aggagauua 19
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gggagauguu uguccuaaa 19
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gguugaugag cuacgccga 19
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guaugucgac gcgcucaua 19
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<213> 人工序列(Artificial sequence)
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acccagatca acgtaggca 19
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tctctgcgca tccttcgag 19
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ggagctcact caaatcccac 20
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atgctaactt cccacatttg g 21
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cgctccccag gattacca 18
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gtgaaaaaga ccacaaattt gga 23

Claims (7)

1.一种抑制DDX17相关RNA表达产物的核苷酸，其特征在于其序列CGCCGAAAGAAGGAGAUUA(SEQ ID NO.1) 或GGGAGAUGUUUGUCCUAAA(SEQ ID NO.2)或者GGUUGAUGAGCUACGCCGA(SEQ ID NO.3)其互补序列。
2.根据权利要求1所述的核苷酸，其特征在于所述核苷酸可被氟代修饰、硫代修饰、甲氧基修饰、胆固醇修饰一种或几种修饰。
3.根据权利要求1至2所述的核苷酸的应用，其特征在于在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用，其特征在于所述肿瘤为肺癌。
5.根据权利要求3所述的应用，其特征在于所述肿瘤为乳腺癌。
6.一种药物组合物，其特征在于包含权利要求 1-2任一项所述的核苷酸和其他抗肿瘤治疗药物。
7.根据权利要求6所述药物组合物，其特征在于其他抗肿瘤治疗药物为三氧化二砷。
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