CN104099333B - 用于乳腺癌的piRNA - Google Patents
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Abstract
本发明提供了一种用于乳腺癌的piRNA，其来自人乳腺癌细胞，包含SEQID NO.1所示序列，定位于人染色体1q25，其前体序列为snoRNA。Northern blot和定量RT‑PCR检测结果表明该piRNA在乳腺癌组织中低表达。本发明提供的piRNA可用于制备治疗乳腺癌疾病的药物。例如，采用基因治疗的方法，以质粒或者病毒为表达载体，使其在癌变部位高效表达。
Description
技术领域
本发明属于分子生物学及生物医药技术领域，涉及人源piRNA寡核苷酸序列以及其在制备治疗乳腺癌疾病药物中的用途。
背景技术
piRNA（PIWI-interacting RNA）是一类具有26～32nt的RNA分子，经由其前体分子在酶的作用下加工生成的，其前体序列一般为长链非编码RNA（long non-coding RNA,lncRNA），目前认为piRNA的功能是参与生命的一些基本过程，如分化发育等，越来越多的证据表明piRNA在细胞中起着调控基因表达的重要作用。最近的研究发现piRNA与肿瘤的发生发展有紧密的相关性，一些piRNA可以显著的抑制肿瘤生长。肿瘤相关的piRNA的发现可能会对肿瘤的基因治疗产生重大的影响。通过对肿瘤和正常组织的小RNA高通量测序分析，可以鉴定肿瘤相关的piRNA，通过引入对肿瘤细胞过表达小RNA可以有效抑制肿瘤的生长。因此，发现肿瘤细胞中的piRNA 以及基于piRNA的肿瘤治疗具有十分重要的意义。
近四十年来关于肿瘤学的大量而迅速的研究，极大扩展了我们对于肿瘤理解的深入程度以及复杂性。肿瘤疾病涉及到整个基因组动态改变的复杂过程，比如各种突变引起的抗癌基因与促癌基因功能的紊乱。乳腺癌是全球高发肿瘤类型之一。尽管目前一些治疗手段可以帮助大多数肿瘤患者缓解痛苦，但乳腺癌仍极大威胁着女性生命安全，导致生活质量下降。每一年，全世界范围内有超过一百三十万的乳腺癌新发病例，有四十五万人死于此病症。建立发现更多的新的可以用于乳腺癌预防及治疗的靶点有重大意义，也仍面临着巨大挑战。
发明内容
本发明的目的是提供一种piRNA寡核苷酸序列及其在制备治疗乳腺癌疾病药物中的用途。
本发明以人乳腺癌和癌旁组织为材料进行deep-sequencing 的小分子RNA高通量测序以及mRNA芯片表达谱分析，采用分子生物学以及生物信息学常规技术进行试验以及分析，得到了一条28nt的RNA分析，经过Blast比对，Northern blot杂交，及RNA共沉淀实验得到证实其为piRNA分子，命名为pi-sno75。Pi-sno75是由其前体snoRNA75在细胞内经过加工后形成的成熟体，经过基因序列的同源性分析获得snoRNA的前体RNA序列。此外，针对该piRNA序列设计其2’-O-甲基化修饰的化学合成小分子RNA，并研究其对乳腺癌细胞生长的影响进行了分析。
本发明所提供的piNA来自人乳腺癌细胞，成熟piRNA序列长度为28nt，其前体序列为snoRNA。Northern blot和定量RT-PCR检测结果表明该piRNA在乳腺癌组织中低表达。构建pi-sno75高表达的乳腺癌细胞系，结果表明在与多柔比星联用条件下，可以显著抑制乳腺癌细胞的生长增殖。基于上述工作本发明得以完成。
具体的说，本发明所提供的人源piRNA——pi-sno75包含如下序列：5’-GGGAUUUCUGAAAUUCUAUUCUGAGGCU-3’ ，定位于人染色体1q25。其中，序列中的U可用T替换。
本发明所提供的人源piRNA可采用化学合成的方法得到，为增强其稳定性，生物利用度等药学特征，可对其进行氧甲基化修饰。
本发明提供的piRNA可用于制备治疗乳腺癌疾病的药物。例如，采用基因治疗的方法，以质粒或者病毒为表达载体，使其在癌变部位高效表达。
附图说明
图1、Northern blot检测pi-sno75在乳腺癌组织中的表达；
图2、定量PCR检测pi-sno75在乳腺癌及癌旁组织中的表达；
图3、过表达pi-sno75及联合应用多柔比星抑制MCF7细胞的增殖（其中A为过表达pi-sno75对MCF7细胞增殖的抑制作用，B为过表达pi-sno75及联合应用多柔比星对MCF7细胞增殖的抑制作用）；
图4、pi-sno75过表达细胞系在体内与多柔比星联合给药对乳腺癌的抑制效果。
具体实施方式
下面结合实施例对本发明作进一步的说明，但并不局限于此。
实验一 乳腺癌组织以及癌旁组织的deep-sequencing 以及乳腺癌中pi-sno75表达的Northern blot验证
我们从中山大学附属第一医院女性乳腺癌患者术后摘除肿瘤组织中，分离500mg肿瘤组织以及200mg癌旁组织。分离后液氮冷冻保存。研磨均匀的组织 (<100 mg)加1mLTrizol溶解，吹打至散，室温放置5分钟；加氯仿200μl，剧烈振荡60秒；静置5分钟，然后4℃，12000g，离心15分钟；转移上清到新的EP管中，加异丙醇500μl，混匀，放置10分钟；4℃，12000g，离心10分钟；弃上清，加75％乙醇1000μl，洗两次，4℃，12000g，离心5分钟； 弃上清，室温干燥。用DEPC水溶解RNA，检测纯度和浓度。样品合格后，寄到深圳华大基因公司做小分子RNA深度测序，测定小分子RNA长度范围是18-40bp。测序结果由华大公司进行分析比对。其中得到一条来自snoRNA75的piRNA序列（如SEQ ID NO.1所示），命名为pi-sno75。长度为28nt。以【γ-32P】ATP标记pi-sno75反向互补LNA杂交检测探针，按照常规Northern blot方法检测pi-sno75在人乳腺癌细胞中的表达。由图1可知，pi-sno75在乳腺癌组织的中确实有表达。
实验二 乳腺癌组织以及癌旁组织中pi-sno75表达情况分析
以乳腺癌组织以及对应癌旁组织为材料，利用上述方法提取RNA，按照TakaraRT反转录试剂盒进行反转录试验，cDNA产物利用Takara SYBR real-time试剂盒进行定量PCR检测。GAPDH作为内参。成对T-test进行统计学分析。由图2可知，pi-sno75在乳腺癌的表达较其癌旁组织中的表达要低。
实验三 体外pi-sno75对乳腺癌细胞系MCF7诱导凋亡情况检测
人的MCF7细胞培养在10%血清浓度的DMEM（Dμlbecco's modified Eagle'smedium）中。采用Lipofectamine RNAiMAX (Invitrogen)转染试剂进行小RNA转染。具体操作按照使用说明进行。转染后36h加入多柔比星5μM。MCF细胞用不含EDTA的胰酶消化收集，用PBS洗涤细胞二次（2000rpm离心5min）收集1～5×105细胞；加入500μL的Binding Buffer悬浮细胞；加入5μL Annexin V-FITC混匀后，加入5 μL Propidium Iodide，混匀；室温、避光、反应5～15min，然后进行流式细胞仪的观察和检测（激发波长Ex=488 nm；发射波长Em=530 nm；荧光补偿调节：使用未经凋亡诱导处理的正常细胞，作为对照进行荧光补偿调节去除光谱重叠和设定十字门的位置），结果显示在多柔比星存在条件下，pi-sno75显著引起凋亡（见图3）。
实验四 体内pi-sno75对乳腺癌细胞系MCF7诱导凋亡情况检测
构建过表达pi-sno75的乳腺癌细胞系，利用上边的质粒，包含pi-sno75的内含子片段插入在慢病毒载体中，其位置处于CMV启动子之后，ires-gfp之前。构建好的pHIV-cPPT-GFP-pi-sno75与空白载体，分别同pCMV-∆R8.2 和pCMV-VSV-G共转染HEK293T包装假病毒，之后用PEG6000浓缩病毒，感染MCF7细胞。流式分选GFP阳性细胞（FACS Aria II ，Becton Dickinson），培养扩增。选择5周龄左右的雌性NOD/SCID小鼠，在同一只小鼠的左右两侧乳腺组织附近分别注射等量过表达的pi-sno75细胞系与对照载体细胞系。当成瘤直径大小在5mm左右时，每周通过小鼠尾静脉注射doxorubicin（2mg/kg）。给药后，肿瘤的生长速度变慢，在首次给药四周后，我们从小鼠体内取出肿瘤及称量湿重。Pi-sno75过表达的细胞系成瘤大小比空白载体显著性的小，且质量轻（见图4）。
综合细胞实验与动物模型实验，pi-sno75在于抗肿瘤药物联合使用下，体内体外结果表明可以显著诱导乳腺癌凋亡并抑制肿瘤增殖。
<110> 中山大学
<120> 用于乳腺癌的piRNA
<130>
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 28
<212> RNA
<213> human
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Claims (6)
1.一种piRNA，其序列如下所示：
5’-GGGAUUUCUGAAAUUCUAUUCUGAGGCU-3’。
2.含有权利要求1所述piRNA的质粒或病毒载体。
3.权利要求1所述的piRNA在制备治疗乳腺癌疾病的制剂或药物中的应用。
4.权利要求1所述的piRNA和其他抗肿瘤药物联用在制备治疗乳腺癌疾病的制剂或药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述其他抗肿瘤药物为多柔比星。
6.权利要求2所述的质粒或病毒载体在制备治疗乳腺癌疾病的制剂或药物中的应用。
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| CA3047027A1 (en) | 2016-12-14 | 2018-06-21 | Shanghaitech University | Compositions and methods for treating cancer by inhibiting piwil4 |
| CN106916885B (zh) * | 2017-01-13 | 2021-11-12 | 青岛大学 | 用于检测心脏病的piRNA组合及其应用 |
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| CN112646892B (zh) * | 2020-12-30 | 2022-02-01 | 广州医科大学附属第三医院（广州重症孕产妇救治中心、广州柔济医院） | 一组乳腺癌早期诊断的piRNA生物标志物及其应用 |
| CN113230268B (zh) * | 2021-05-10 | 2023-02-21 | 上海市东方医院（同济大学附属东方医院） | 一种非编码小rna基因、载体和细胞在制备抑制乳腺癌的药物中的用途 |
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