CN116254343B - Rp11-713m15.2在制备治疗癌症的药物中的用途 - Google Patents
Rp11-713m15.2在制备治疗癌症的药物中的用途 Download PDFInfo
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C12Q2600/00—Oligonucleotides characterized by their use
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Abstract
本发明提供RP11‑713M15.2作为生物标志物在制备治疗癌症的药物中的用途，本发明发现了LIST在肿瘤发生发展和耐药中的功能，并揭示其具体的分子机制，发现LIST在制备核酸药物方面具有潜在的前景。
Description
技术领域
本发明涉及生物医药领域，具体涉及RP11-713M15.2作为生物标志物在制备治疗癌症的药物中的用途。
背景技术
长期以来，肿瘤耐药性研究一直是肿瘤研究的热点问题，但如何靶向调控肿瘤耐药，目前仍没有特别有效的手段。Src基因是哺乳动物中发现的第一个原癌基因，其编码的蛋白质是一种非受体型酪氨酸激酶(人类中基因产物为c-Src)[1]。细胞在静息状态时，c-Src在Tyr530位点发生磷酸化(CSK，CHK激酶激活)，并与自身的SH2结构域结合产生分子卷曲，导致酶活性中心被遮盖，c-Src以失活形式存在[2]；当细胞接收到外界信号刺激时，磷酸酶(PTPα，PTPλ)会与c-Src结合并使Tyr530位点发生去磷酸化，此时，c-Src构象发生改变，Tyr419发生自身磷酸化，进而激活c-Src[3，4]。因此，Y530上的去磷酸化是c-Src启动激活和传导信号的关键步骤。
研究表明，c-Src在人类多种恶性肿瘤中存在异常激活现象(发生Y530去磷酸化)，抑制c-Src在Y530位点的磷酸化可以显著促进肿瘤的发生发展和耐药过程[5,6]，这使得它成为一个非常有价值的抗癌治疗靶点，目前已有多个针对c-Src的激酶抑制剂进入临床实验阶段[7-9]。然而临床研究发现c-Src抑制剂和化疗药物的联合治疗效果也不理想和稳定，容易产生耐药性。比如博舒替尼(c-Src抑制剂)和来曲唑联合治疗乳腺癌患者，初期虽然有一定疗效，但很容易产生化疗耐药性[10]；此外，在c-Src抑制剂AZD0530治疗非小细胞肺癌和前列腺癌的临床试验中也出现了类似的继发耐药现象[11，12]。因此，急需深入探索c-Src在肿瘤获得性耐药中的作用机制，为研发高效的c-Src抑制剂提供理论依据。
发明内容
根据第一方面，在一实施例中，提供RP11-713M15.2基因(本文命名为LIST)或其lncRNA作为生物标志物在制备预防或治疗癌症的药物中的用途。
根据第二方面，在一实施例中，提供RP11-713M15.2基因或其lncRNA作为生物标志物在制备抑制癌细胞的增殖和/或化疗耐药的药物中的用途。
根据第三方面，在一实施例中，提供RP11-713M15.2基因或其lncRNA作为生物标志物在制备c-Src激动剂中的用途。
根据第四方面，在一实施例中，提供RP11-713M15.2基因或其lncRNA作为生物标志物在制备癌症检测试剂中的用途。
在一实施例中，本发明发现了LIST在肿瘤发生发展和耐药中的功能，并揭示其具体的分子机制，发现LIST在制备核酸药物方面具有潜在的前景。
在一实施例中，本发明鉴定并明确了LIST是一种新型高效的c-Src激动剂，发现LIST可以用于制备高效的c-Src激动剂。
附图说明
图1为LIST的筛选结果图；
图2为LIST的癌症基因组图谱(TCGA)数据分析结果；
图3为LIST的细胞水平研究结果；
图4为LIST的动物水平研究结果；
图5为LIST的功能机制研究结果。
具体实施方式
下面通过具体实施方式结合附图对本发明作进一步详细说明。在以下的实施方式中，很多细节描述是为了使得本申请能被更好的理解。然而，本领域技术人员可以毫不费力的认识到，其中部分特征在不同情况下是可以省略的，或者可以由其他材料、方法所替代。在某些情况下，本申请相关的一些操作并没有在说明书中显示或者描述，这是为了避免本申请的核心部分被过多的描述所淹没，而对于本领域技术人员而言，详细描述这些相关操作并不是必要的，他们根据说明书中的描述以及本领域的一般技术知识即可完整了解相关操作。
另外，说明书中所描述的特点、操作或者特征可以以任意适当的方式结合形成各种实施方式。同时，方法描述中的各步骤或者动作也可以按照本领域技术人员所能显而易见的方式进行顺序调换或调整。因此，说明书和附图中的各种顺序只是为了清楚描述某一个实施例，并不意味着是必须的顺序，除非另有说明其中某个顺序是必须遵循的。
本文中为部件所编序号本身，例如“第一”、“第二”等，仅用于区分所描述的对象，不具有任何顺序或技术含义。
近些年随着测序技术的快速发展，研究发现人类基因组上大量的非编码区会转录出没有翻译活性的长链非编码RNA(lncRNA)，且数量远远超过蛋白。研究表明，长链非编码RN A(long non-coding RNA,lncRNA)可以通过表观遗传调控、转录调控和转录后调控等方式调节基因的表达，从而在多种生命活动中发挥重要作用[19-21]。因此lncRNA的功能和作用机制具有多样性，比如细胞核中的lncRNA可以顺式调控相邻基因的表达，也可以离开转录位点调控远端基因的表达或染色体的结构；细胞质中的lncRNA可以与microRNA结合靶向调节mRNA的表达，或者与蛋白质结合调控其翻译后修饰过程[22-24]。这表明lncRNA在行使功能时不是执行者而是作为辅助因子去调控功能蛋白的表达或活性。因此，针对lncRNA设计药物靶点的策略已逐步在药物设计和开发中广泛应用。基于此研究现状，本发明希望从表观调控角度出发，探索肿瘤细胞内是否存在直接调控c-Src活性的lncRNA。
当前，靶向c-Src的药物多为小分子化合物，但治疗过程中肿瘤细胞常常会通过靶蛋白的新突变等获得耐药性，临床试验效果不理想且不稳定。因此，本发明从表观遗传调控角度，以寻找直接调控c-Src活性的lncRNA为切入点，利用高通量测序分析并结合分子生物学实验筛选到一个可以直接结合c-Src并调控其磷酸化的lncRNA-LIST。进一步研究发现LIST通过阻断c-Src与激酶的结合，作为c-Src激动剂发挥促肿瘤功能。
根据第一方面，在一实施例中，提供RP11-713M15.2基因(本文命名为LIST)或其lncRN A作为生物标志物在制备预防或治疗癌症的药物中的用途。
在一实施例中，所述RP11-713M15.2基因或其lncRNA用于制备抑制c-Src-Y530位点的去磷酸化的药物。
在一实施例中，所述RP11-713M15.2基因或其lncRNA用于直接结合并激活c-Src蛋白的活性。
在一实施例中，通过敲低所述RP11-713M15.2基因或其lncRNA，抑制c-Src蛋白的活性。
在一实施例中，所述RP11-713M15.2基因或其lncRNA用于制备直接结合并激活c-Src蛋白的活性的药物。
在一实施例中，所述RP11-713M15.2基因或其lncRNA在癌细胞中相对于在正常细胞中高表达。
在一实施例中，所述RP11-713M15.2基因或其lncRNA用于制备抑制癌细胞的增殖和/或化疗耐药的药物。
在一实施例中，通过敲低所述RP11-713M15.2基因或其lncRNA表达，抑制癌细胞的增殖和/或化疗耐药。
在一实施例中，所述药物还包括化疗药物。本发明发现，RP11-713M15.2基因或其lncR NA与化疗药物联合使用，可以协同抗肿瘤。
在一实施例中，所述化疗药物包括但不限于紫杉醇、顺铂中的至少一种。
在一实施例中，所述RP11-713M15.2基因或其lncRNA通过1-120nt序列与c-Src蛋白的unique结构域结合。
在一实施例中，所述RP11-713M15.2基因或其lncRNA通过562-682nt序列与c-Src蛋白的SH1-C结构域结合。
在一实施例中，所述RP11-713M15.2基因或其lncRNA用于制备减弱c-Src蛋白与CHK激酶和/或CSK激酶的结合的药物。
在一实施例中，通过过表达所述RP11-713M15.2基因或其lncRNA减弱c-Src蛋白与CH K激酶和/或CSK激酶的结合。
在一实施例中，所述RP11-713M15.2基因或其lncRNA与c-Src蛋白结合，通过减弱或阻断c-Src蛋白与CHK激酶和/或CSK激酶的结合，封闭c-Src-Y530位点的磷酸化，进而发挥激酶活性。
在一实施例中，所述RP11-713M15.2基因或其lncRNA用于制备c-Src激动剂。
在一实施例中，所述癌症包括但不限于肺腺癌、膀胱癌、黑色素瘤、肺鳞癌、肾透明细胞癌、前列腺癌、宫颈癌、肾乳头状细胞癌、肝细胞癌、胃癌、头颈鳞状细胞癌、胆管癌、乳腺癌、直肠癌、结肠腺癌、胰腺癌、子宫内膜癌、食道癌、肉瘤样肺癌、甲状腺癌、嗜铬细胞瘤和副神经节瘤、多形成性胶质细胞瘤中的至少一种。
在一实施例中，所述癌症包括肺腺癌、膀胱癌、黑色素瘤、肺鳞癌、肾透明细胞癌、前列腺癌、宫颈癌、肾乳头状细胞癌、肝细胞癌、胃癌、头颈鳞状细胞癌、胆管癌、乳腺癌、直肠癌中的至少一种。
在一实施例中，所述癌症包括肺腺癌、膀胱癌中的至少一种。
根据第二方面，在一实施例中，提供RP11-713M15.2基因或其lncRNA作为生物标志物在制备抑制癌细胞的增殖和/或化疗耐药的药物中的用途。
在一实施例中，所述癌包括但不限于肺腺癌、膀胱癌、黑色素瘤、肺鳞癌、肾透明细胞癌、前列腺癌、宫颈癌、肾乳头状细胞癌、肝细胞癌、胃癌、头颈鳞状细胞癌、胆管癌、乳腺癌、直肠癌、结肠腺癌、胰腺癌、子宫内膜癌、食道癌、肉瘤样肺癌、甲状腺癌、嗜铬细胞瘤和副神经节瘤、多形成性胶质细胞瘤中的至少一种。
根据第三方面，在一实施例中，提供RP11-713M15.2基因或其lncRNA作为生物标志物在制备c-Src激动剂中的用途。
根据第四方面，在一实施例中，提供RP11-713M15.2基因或其lncRNA作为生物标志物在制备癌症检测试剂中的用途。
实施例
本实施例的具体设计方案流程如下：
1.LIST的筛选
我们首先通过RNA结合蛋白免疫沉淀试验并结合RNA测序，寻找膀胱癌5637细胞中与c-Src结合的lncRNA。然后选择fold change≥3的lncRNAs进行活性筛选(图1A)。通过监测细胞活力，我们筛选出了5个lncRNAs可以调节细胞对c-Src抑制剂的敏感性(图1B)。因为Y530位点的去磷酸化是c-Src发挥功能的必要条件，我们进一步检测发现只有RP11-713M15.2(我们命名为LIST)可以维持c-Src-Y530位点的去磷酸化(图1C)。免疫荧光实验进一步显示c-Src与LIST存在共定位现象(图1D)。这说明LIST可以直接结合并激活c-Src的活性。
2.LIST的细胞水平研究
LIST位于人类第8号染色体上，包含一个单独的外显子，其转录本长度为1.129kb。我们利用癌症基因组图谱(TCGA)的数据分析发现LIST在多种肿瘤中的表达要高于相对应的正常组织(图2)。尤其在膀胱癌和肺癌中差异最显著。因此我们选择5637(膀胱癌，中科院上海细胞库)和A549(肺癌，中科院上海细胞库)两种细胞系，构建LIST过表达的稳筛细胞株。具体地，首先进行病毒包装，将293T细胞(中科院上海细胞库)接种于75mm培养瓶，第二天进行转染，取1mL opti-MEM培养基稀释10μL脂质体Lipofectamine 2000(ThermoFisher，11668019)，取1mL opti-MEM培养基稀释表达载体和包装载体(一共12μg，按质量计，plv-LIST：pLP1:pLP1:pLP-VSVG＝4:3:2:3)，然后将其混匀，静止孵育20min，然后将其缓慢滴入含有细胞的培养皿中，加培养基补充至10mL，48小时后收取上清，3000rpm离心10min，此上清即为病毒液，分装放-80℃备用。对于构建LIST过表达的稳筛细胞株，首先将细胞种于6孔板中，第二天加入500μL病毒液，加培养基补充至2mL，48小时后加入嘌呤霉素去除没有表达病毒的细胞，三天加一次嘌呤霉素，如此持续筛选两组就得到稳转细胞系，通过RT-qPCR检测其敲低效率，过表达效率见图3A。结果发现LIST表达能明显促进细胞的增殖和化疗耐药(图3B-C)。
图2中，各癌种的简称说明如下：LUAD：肺腺癌，BLCA：膀胱癌，SKCM：黑色素瘤，LUSC：肺鳞癌，KIRC：肾透明细胞癌，PRAD：前列腺癌，CESC：宫颈癌，KIRP：肾乳头状细胞癌，LIHC：肝细胞癌，STAD：胃癌，HNSC：头颈鳞状细胞癌，CHOL：胆管癌，BRCA：乳腺癌，READ：直肠癌，COAD：结肠腺癌，PAAD：胰腺癌，UCEC：子宫内膜癌，ESCA：食道癌，SARC：肉瘤样肺癌，THCA：甲状腺癌，PCPG：嗜铬细胞瘤和副神经节瘤，GBM：多形成性胶质细胞瘤。
从图2可见，LIST在排名前14的肿瘤中均有表达差异，在肺腺癌(LUAD)和膀胱癌(BLCA)中差异最显著。
我们选择耐药细胞株5637-GEM(人膀胱癌吉西他滨耐药细胞株)和A549-DDP(人肺腺癌耐顺铂细胞株)，对其进行LIST稳定敲低，方法见上文慢病毒包装和稳转细胞系构建，敲低效率见图3D。发现能抑制细胞的增殖和化疗耐药(图3E-F)。图3中，shNC为阴性对照。为防止脱靶效应，针对LIST设计两个shRNA敲低：shLIST-1和shLIST-2。
shLIST-1Sense 5'-3'：GCAATCCAGAAATGCCCACAT(SEQ ID NO:1)。
Antisense 5'-3'：ATGTGGGCATTTCTGGATTGC(SEQ ID NO:2)。
shLIST-2Sense 5'-3'：GCAAGGTGTTGAGAGGAAATA(SEQ ID NO:3)。
Antisense 5'-3'：TATTTCCTCTCAACACCTTGC(SEQ ID NO:4)。
shNC(negative control)Sense 5'-3'：ACGTGACACGTTCGGAGAAA(SEQ ID NO:5)。
Antisense 5'-3'：TTTCTCCGAACGTGTCACGT(SEQ ID NO:6)。
3.LIST的动物水平研究
我们进一步探究LIST对肿瘤细胞成瘤能力的影响。我们把LIST稳定敲低的5637-GEM细胞和对照组细胞注射到无胸腺裸鼠(BALB/c裸鼠，雄性)的皮下。对于加药组，采用紫杉醇(PTX，0.4mg/kg)每4天腹腔注射一次，顺铂(DDP，3mg/kg)每4天腹腔注射一次。用游标卡尺每周进行肿瘤块大小的测量，培育5周后将肿瘤取出测量其重量和体积，结果发现LIST敲低的细胞形成的肿瘤块其体积和重量要明显低于对照组，而LIST敲低和化疗药物同时处理后，肿瘤的体积和重量最小，说明二者具有协同抗肿瘤功能(图4A)。相应地，我们构建LIST过表达的稳筛细胞株，注射到无胸腺裸鼠的皮下，培育5周后进行相同操作处理，结果发现LIST过表达的细胞形成的肿瘤块的重量和体积要明显大于对照组，而在加药组中，LIST过表达的细胞形成的肿瘤块其重量和体积要明显大于对照组(图4B)。
4.LIST的功能机制研究
我们初步确定了LIST可以结合并抑制c-Src-Y530位点的磷酸化。我们构建了一系列LI ST截断体，通过RNA结合蛋白免疫沉淀实验发现LIST主要通过1-120nt和562-682nt两个区域与c-SRC结合(图5A)。c-Src蛋白含有4个结构域，我们分别构建相应的截断体，通过RNA结合蛋白免疫沉淀实验发现c-Src通过unique结构域和SH1-C结构域和LIST结合(图5B)。最后通过体外RNA-蛋白结合实验发现LIST通过1-120nt与c-Src的unique结构域结合，通过562-682nt与c-Src的SH1-C结构域结合(图5C)。已知CHK和CSK可以结合c-Src并促进其Y530磷酸化。我们通过免疫共沉淀实验发现过表达LINC1089可以减弱c-Src与CHK和CSK的结合(图5D)。这表明LIST与c-Src结合通过阻断c-Src与CHK和CSK的结合，封闭c-Src-Y530位点的磷酸化，进而发挥其激酶活性，所有LIST可以作为特异的c-Src激动剂。
LIST基因序列如下：
CAACCCAGCGGCCGCTCACCTGTTCCAGCCGCCGCAGCCTCGGCGGTCACACGCC
ACCCGCCCGCCCAGACCTCCCCTCCTCTGTCCCCAGAGCGCACGACGCCGCGGGGACA
GCTTCCCGAGCGCCTTCCCCGTCCCGCTTCTCTCCAGCCCACCGCAGCCCCCTTTCTTCC
CAGCTCCCCCACTCCGTGGGCGCCCACACTGCACCTTCGCCGGGTGCGTGCGTCCCGCC
TCGGTGCCCTCACTCGGTCCTCCTGAGCCGACTTCCCTTTCATACCCAGCCCGTAGAATT
GTCCCTGGGTCTTAACAACTCATTTGTAACTGATCCAGGTCTCCTCCCTCTGCTTCCTCA
AACCCAGGCTTCGCTGCCTCTGCGGAGTTCTTACCTGTCTCTCCTTTCCACCCGGGTTCC
CTGGAGGAAGCTAAACTCAGACCAAGGCCCTGGGCTCCCCAGGAGTTAAAAGGGAATA
CGCTGTCCCAAGATTCTAGAATGAAGAGTCAACGTAGCCCGAGTGGCTTAAACCTCCTG
TCCTTAAATGCAAGAAATGTTTTCTATCGAGCCCTGGACAGGTGTCTCTGCTGGCCTGGG
GTTTTCAACAGGTCATGCCTGCCTCAGACCCCAGGGACAAATGTTCTTCCAGCTCTAAC
TCATTCTATGCTTTAAGCTTTTGACCTATCTTTGTTTTCCCAGTGCCACACCAAATGCTGC
CTGGGGATCTCTCTTTCTTCCTGAGTTCCCATATAAGAAGCCCCCCATTTAAGAATTCAGT
TGGAATGGGTTGTATTTCAAAAGTTGCTTTGCAAGTTAGTTATTTGGATTTCAAGTTGCAT
TTTACCAGGGTAACAATATTATAATGATTGTTTACCTTCCCAGAGCAATCCAGAAATGCCC
ACATAACCCATGTCACACCTGAACCACCCTGAGTTCTTCTATCCTTGAACCTCTCAAGCT
TTCCCCTAACTCTAAGCAGGTCTCATGGTCCACTCAAGGTGTTTCATGCTTCTCAGTTAC
GTCCCCTTCCCACTGCTGTCTACCCTCTCTCCAAACACAACACAAAACAAACCCACAAC
AGTTCTGTTAATTCCTGAAGTAAACCCAACCCAGCAAGGTGTTGAGAGGAAATAAATC
(SEQ ID NO:7)。
在一实施例中，本发明发现了LIST在肿瘤发生发展和耐药中的功能，并揭示其具体的分子机制，发现LIST在制备核酸药物方面具有潜在的前景。
在一实施例中，本发明鉴定并明确了LIST是一种新型高效的c-Src激动剂，发现LIST可以用于制备高效的c-Src激动剂。
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24.Statello L,Guo CJ,Chen LL,Huarte M:Gene regulation by long non-coding RN As and its biological functions.Nat Rev Mol Cell Biol 2021,22(2):96-118.
以上应用了具体个例对本发明进行阐述，只是用于帮助理解本发明，并不用以限制本发明。对于本发明所属技术领域的技术人员，依据本发明的思想，还可以做出若干简单推演、变形或替换。
Claims (12)
1.用于抑制RP11-713M15.2基因表达的shLIST-1和shLIST-2在制备治疗肺腺癌或膀胱癌药物中的用途，其中：shLIST-1 Sense的核苷酸序列如SEQ ID NO:1所示， shLIST-2Sense的核苷酸序列如SEQ ID NO:3所示。
2.如权利要求1所述的用途，其特征在于，所述shLIST-1和shLIST-2抑制c-Src蛋白的活性。
3.如权利要求2所述的用途，其特征在于，所述shLIST-1和shLIST-2通过敲低RP11-713M15.2基因，抑制c-Src蛋白的活性。
4.如权利要求1所述的用途，其特征在于，所述RP11-713M15.2基因在癌细胞中转录表达量高于正常细胞。
5.用于抑制RP11-713M15.2基因表达的shLIST-1和shLIST-2在制备用于抑制癌症细胞的增殖的药物中的用途，所述癌症为肺腺癌或膀胱癌, 其中：shLIST-1 Sense的核苷酸序列如SEQ ID NO:1所示， shLIST-2 Sense的核苷酸序列如SEQ ID NO:3所示。
6.用于抑制RP11-713M15.2基因表达的shLIST-1和shLIST-2在制备用于抑制膀胱癌癌细胞吉西他滨耐药的药物中的用途，其中：shLIST-1 Sense的核苷酸序列如SEQ ID NO:1所示， shLIST-2 Sense的核苷酸序列如SEQ ID NO:3所示。
7.用于抑制RP11-713M15.2基因表达的shLIST-1和shLIST-2在制备用于抑制肺腺癌癌细胞顺铂耐药的药物中的用途，其中：shLIST-1 Sense的核苷酸序列如SEQ ID NO:1所示，shLIST-2 Sense的核苷酸序列如SEQ ID NO:3所示。
8.如权利要求5所述的用途，其特征在于，所述shLIST-1和shLIST-2通过敲低RP11-713M15.2基因，抑制癌细胞的增殖。
9.如权利要求6或7所述的用途，其特征在于，所述shLIST-1和shLIST-2通过敲低RP11-713M15.2基因，抑制癌细胞的化疗耐药。
10.如权利要求1所述的用途，其特征在于， 所述RP11-713M15.2基因转录生成的lncRNA通过1-120nt序列与c-Src蛋白的unique结构域结合。
11.如权利要求1所述的用途，其特征在于，所述RP11-713M15.2基因转录生成的lncRNA通过562-682nt序列与c-Src蛋白的SH1-C结构域结合。
12.检测RP11-713M15.2基因转录生成的lncRNA的表达水平的试剂在制备膀胱癌或肺腺癌检测试剂中的用途。
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