CN110272997B - 一种C/EBPβ基因或者蛋白的用途 - Google Patents
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Abstract
本发明公开了一种C/EBPβ基因或者蛋白的用途。所述C/EBPβ基因或者蛋白在制备评估肿瘤耐药风险和/或患者预后的生物标志物中的用途，所述的肿瘤为卵巢癌或者乳腺癌。本发明从新的角度研究肿瘤细胞的耐药机制，发现C/EBPβ通过重编程众多耐药基因的表达从而介导化疗耐药，并且揭示了DOT1L是介导C/EBPβ调控作用的组蛋白甲基转移酶。本发明为评估卵巢癌或者乳腺癌的耐药风险以及患者预后，以及针对卵巢癌或者乳腺癌药物的筛选提供了依据。为癌症，特别是卵巢癌和乳腺癌的分子靶向治疗提供了新的、更为精准的靶点，为筛选适合顺铂联合化疗的药物(新型酶抑制剂)奠定了基础。
Description
技术领域
本发明属于生物医药领域，具体涉及卵巢癌耐药领域，特别涉及一种C/EBPβ基因或者蛋白的用途。
背景技术
化疗是目前临床肿瘤治疗中最重要的手段之一，通常可在一定时间内取得较好的治疗效果。然而，在治疗过程中，肿瘤细胞逐渐产生耐药性，使化疗的效果受到很大制约。卵巢癌是致死率最高的妇科肿瘤，其起病过程隐匿，70％的患者在初次诊断时已是晚期。肿瘤细胞减灭术和术后以铂类为主的化疗是目前卵巢癌的主要治疗方案。然而，由于大多数病人最终都发展为化疗耐药，晚期卵巢癌患者的5年生存率小于30％。50多年来，卵巢癌患者的预后没有明显改善(Nat Rev Cancer,2011,11(10):719-725；Annu Rev Pathol,2014,9:27-45)。因此，目前亟待阐明新的耐药机制和发现新的治疗靶点，从而增强化疗敏感性，提高治疗效果。
耐药基因(drug-resistance genes)的表达是肿瘤细胞获得耐药性的关键(Ann NY Acad Sci,2012,1271:58-67；Yonago Acta Med,2013,56(2):43-50)。以往研究多注重具体耐药基因的作用机制，然而，肿瘤细胞的耐药性涉及多种机制，包括转运能力增强(降低细胞内药物浓度)、解毒作用增强(促进药物失活)、DNA修复能力增强、凋亡抵抗能力增强等等(Yonago Acta Med,2013,56(2):43-50；Arch Biochem Biophys,2010,500(2):116-122；Cell Cycle,2014,13(1):42-51)。这种复杂的表型是由多种耐药基因决定的，因此，单一耐药基因很难成为理想的治疗靶点。能够调控多个耐药基因表达的调控因子则有可能成为理想的治疗靶点。目前尚不清楚是否存在能够调控众多耐药基因表达的关键调控因子，以及这种因子是否可能成为逆转耐药的治疗靶点。
表观遗传学调控是能够同时改变众多基因表达的重要机制。表观遗传学指的是在基因序列不发生改变的情况下，基因表达的可遗传的变化。在肿瘤发生发展过程中，会发生众多基因表达的变化，其机制常常与表观遗传学改变有关，如组蛋白修饰和DNA甲基化(CACancer J Clin,2010,60(6):376-392；Front Oncol,2014,4:71)。组蛋白和/或DNA的修饰可导致稳定性的基因表达谱变化，被称为“表观重编程”(epigenetic reprogramming)，是调控肿瘤表型的重要机制，如增强细胞增殖能力、侵袭能力等(CA Cancer J Clin,2010,60(6):376-392；Carcinogenesis.2010,31(1):27-36)。表观遗传学调控因子能够调控众多癌基因或抑癌基因的表达，如重塑许多转移相关基因的表达，显著地改变细胞表型，从低转移表型转变为高转移表型(Nature,2008,452(7184):187-193)。这种表观调控因子的作用非常关键，因而产生了以此类因子为靶点的“表观治疗”(epigenetic therapy)策略(J ClinOncol,2009,27(32):5410-5417；J Clin Invest.2015,125(3):1043-1055；Invest NewDrugs,2014,32(3):526-534；Cancer Discov,2013,3(9):1002-1019)。肿瘤细胞耐药性也涉及到众多基因的表达变化，但目前尚未揭示能够同时调控多个耐药基因表达的重编程机制。因此，找到这种关键调控因子对于化疗耐药的研究和肿瘤的靶向治疗具有重要的意义，特别是卵巢癌和乳腺癌。
发明内容
本发明所要解决的技术问题是为克服现有技术中针对肿瘤治疗过程中易出现耐药性以及预后差等现象缺乏可用于评估肿瘤耐药性、预后的标志物，并且进一步地缺乏抗肿瘤药物的缺陷，提供一种C/EBPβ基因或者蛋白的用途。为评估卵巢癌或者乳腺癌的耐药风险以及患者预后，以及针对卵巢癌或者乳腺癌药物的筛选提供了依据；为恶性肿瘤例如癌症，特别是卵巢癌和乳腺癌的分子靶向治疗提供了新的、更为精准的靶点，为筛选适合顺铂联合化疗的药物(新型酶抑制剂)奠定了基础。
以往关于表观关键调控因子的研究主要集中于表观调控酶。然而，仅仅只有数个，有时只有一个酶催化某一修饰位点。因此，靶向这种调控全基因组所有基因的表观修饰酶往往是不精准的。关于酶的协同因子及其时空特异性和/或基因序列特异性的调控机制是该领域的关键问题，也是难点问题。本发现揭示了表观遗传学调控在肿瘤耐药及其逆转中的作用，证明了C/EBPβ可作为卵巢癌铂类耐药和预后评估的生物标志物。而且本发现提示：除表观修饰酶之外，C/EBPβ这类酶的协同因子可能作为分子靶向治疗中更加精准的新靶点。
本发明主要通过以下技术手段解决上述技术问题：
本发明提供一种C/EBPβ基因或者蛋白在制备评估肿瘤耐药风险和/或患者预后的生物标志物中的用途，所述的肿瘤为卵巢癌或者乳腺癌。
本发明中所述的耐药可为本领域常规的概念，指的是机体对药物反应性降低，优选为化疗药物耐药，所述化疗药物优选为铂类化疗药例如临床常用的顺铂、卡铂等，本发明选择顺铂为例来说明。
若没有特殊说明，本发明所述的卵巢癌可为本领域常规的卵巢癌，优选为浆液性卵巢癌，特别是高级别浆液性卵巢癌。
本发明还提供一种C/EBPβ基因或者蛋白在制备肿瘤耐药或者患者预后的诊断试剂中的用途，所述的肿瘤为卵巢癌或者乳腺癌。如上所述，所述的耐药为化疗药物耐药，所述化疗药物优选为铂类化疗药例如顺铂；所述的卵巢癌优选为浆液性卵巢癌，特别是高级别浆液性卵巢癌。
根据本发明，所述的患者预后优选为卵巢癌或者乳腺癌患者生存时间相关，更优选为卵巢癌患者较短的疾病无进展生存时间(PFS)(1.8年，p＝8.65×10-17)，及较短的总生存时间(2.2年，p＝1.17×10-4)。
本发明还提供一种靶向C/EBPβ或C/EBPβ下游信号的抑制剂、或者靶向C/EBPβ蛋白与H3K79组蛋白甲基化转移酶相互作用的拮抗剂在制备抗卵巢癌或者乳腺癌的药物中的用途。
其中，所述的C/EBPβ基因或者蛋白优选作为逆转肿瘤耐药性的分子靶点。
所述的抑制剂可为本领域常规的、用于抑制或者靶向C/EBPβ或C/EBPβ下游信号的核酸序列或者蛋白，优选为直接靶向C/EBPβ基因或者蛋白、或者C/EBPβ下游信号的siRNA、shRNA或抗体，所述C/EBPβ下游信号优选自下述一种或多种：EGFR、RICTOR、HIF1A、ABCC3、G2E3、NIPBL、NEIL3、ROCK1、多药耐药相关蛋白1[MRP1/ABCC1]以及BRCA1通路，所述的H3K79组蛋白甲基转移酶优选为DOT1L蛋白；较佳地，所述的药物还包括铂类化疗药例如顺铂作为活性成分。
本发明还提供一种C/EBPβ基因作为抗卵巢癌或者乳腺癌药物的筛选标记的用途。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明从新的角度研究肿瘤细胞的耐药机制，发现C/EBPβ通过重编程众多耐药基因的表达从而介导化疗耐药，并且揭示了DOT1L是介导C/EBPβ调控作用的组蛋白甲基转移酶。本发明为评估卵巢癌或者乳腺癌的耐药风险以及患者预后，以及针对卵巢癌或者乳腺癌药物的筛选提供了依据；为癌症，特别是卵巢癌和乳腺癌的分子靶向治疗提供了新的、更为精准的靶点，为筛选适合顺铂等铂类药物联合化疗的药物(新型酶抑制剂)奠定了基础。
附图说明
图1为利用上皮性标志物EPCAM分选获得高纯度的肿瘤细胞和正常上皮细胞。
图2为H3K9和H3K79位点的组蛋白甲基化水平在高级别浆液性卵巢癌中显著增高。
图3为浆液性卵巢癌的组蛋白甲基化与基因表达的关系。
图4为筛选调控组蛋白甲基化的位点特异性转录因子。
图5为C/EBPβ在卵巢癌中高表达并与患者的预后差有关。
图6为C/EBPβ在卵巢癌细胞系中的表达水平与细胞的铂类耐药程度密切相关。
图7为C/EBPβ促进卵巢癌铂类耐药。
图8为C/EBPβ通过调控H3K79甲基化重编程基因表达。
图9为通过募集组蛋白甲基转移酶DOT1L，C/EBPβ促进其靶基因的H3K79甲基化。
图10为C/EBPβ促进卵巢癌铂类耐药的作用依赖于DOT1L。
图11为C/EBPβ下游基因的整合通路分析。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1过表达C/EBPβ可降低细胞对顺铂的敏感性，抑制C/EBPβ表达则增加细胞对顺铂的敏感性
1、甲基化分析
浆液性卵巢癌是最常见、恶性程度最高的卵巢癌。浆液性卵巢癌的组织起源是输卵管上皮。选用上皮性标志物EPCAM、采用磁珠分选方法分别纯化了正常输卵管、高级别浆液性卵巢癌(HG-SOC)和低级别浆液性卵巢癌(LG-SOC)的标本(图1)，对6个主要的组蛋白甲基化位点(H3K4、H3K9、H3K27、H3K36、H3K79和H4K20)进行了分析。采用染色质免疫共沉淀结合高通量测序(ChIP-Sequencing)，分析了各组标本的组蛋白甲基化程度。
结果显示，HG-SOC以H3K4me3、H3K9me3和H3K79me3增高为主，而LG-SOC在各个位点上的甲基化程度变化很小(图2，图3A、3B)。同时采用RNA-Sequencing分析了各组之间表达水平存在显著差异的基因。ChIP-Sequencing联合RNA-Sequencing的结果显示，HG-SOC中许多基因的表达上调与H3K4me3和H3K79me3水平增高有关(图3C)，许多基因表达的下调主要与H3K9me3水平增高有关(图3D)；而LG-SOC中大部分基因表达水平的变化都与组蛋白甲基化程度无关(图3C和3D)。因此，组蛋白的H3K4、H3K9和H3K79甲基化修饰在高级别浆液性卵巢癌的基因表达调控中起重要作用。
2、甲基化修饰的机制研究
组蛋白的甲基化修饰可由多种复杂机制进行控制，其中很重要的一种机制是通过位点特异性的转录因子募集组蛋白甲基转移酶，从而使该转录因子的靶基因发生组蛋白甲基化修饰。本发明着重分析了组蛋白H3K4、H3K9和H3K79甲基化水平增高的基因，采用基序分析(motif analysis)策略对这些基因的序列进行位点特异性转录因子的结合预测。结果显示，在H3K4甲基化水平增高的基因中，有13个基序显著富集，在H3K9、H3K79甲基化水平增高的基因中，分别有9个、15个基序显著富集；与这37个基序结合的转录因子有35个，均已鉴定(图4A)。这些转录因子结合的基序在基因序列中富集，提示这些转录因子很可能参与卵巢癌中组蛋白甲基化修饰的调控。
利用癌症基因组图谱计划(TCGA；Nature.2011；474(7353):609-15)数据库中HG-SOC的数据，进一步通过生存分析来确定上述35个候选转录因子对病人预后的影响。用每个基因的表达水平中位数作为阈值，将患者分成基因-高表达组及基因-低表达组，比较两组间的预后差异。Kaplan-Meier生存分析的结果显示，C/EBPβ高表达组病人的总生存(OS；图4B左图)和疾病无进展生存(PFS；图4B右图)显著较差。更重要的是，转录因子在肿瘤中表达水平变化与预后联合分析的汇总结果显示，在35个候选转录因子中，C/EBPβ是唯一一个与HG-SOC的总生存和疾病无进展生存都有关的因子(图4C)。
采用免疫组化分析了20个正常输卵管、20个正常卵巢上皮和245个高级别浆液性卵巢癌(HG-SOC)病人的标本，并且对卵巢癌病人进行预后随访。结果显示，C/EBPβ的蛋白水平在正常组织中很低，而在高级别浆液性卵巢癌中明显增高(图5A)。C/EBPβ蛋白水平的高表达与卵巢癌患者较短的疾病无进展生存时间(PFS，图5B)及较短的总生存时间(OS，图5C)有关。
采用蛋白印迹检测C/EBPβ在多个卵巢癌细胞系中的蛋白水平，结果显示，C/EBPβ蛋白水平在多种卵巢癌细胞系中明显增高，OV2008是顺铂敏感细胞，C13*是OV2008衍生的顺铂耐药细胞(Cancer Res.2001；61(5):1862-8；Cancer cell international 2009,9:4)，各细胞系之间顺铂耐药程度的差异与C/EBPβ表达水平密切相关(图6)。TCGA(mRNA水平)以及免疫组化的数据分析(蛋白水平)显示，C/EBPβmRNA或蛋白高表达的HG-SOC病人发生顺铂耐药的比例都明显增高(图7a)。在OV2008细胞中过表达了C/EBPβ，并采用shRNA(shC/EBPβ_1,5′-TGCCTTTAAATCCATGGAA-3′；shC/EBPβ_2,5′-ACTTCCTCTCCGACCTCTT-3′)在C13*细胞中沉默C/EBPβ的表达(图7b)确定了C/EBPβ在顺铂耐药中的作用：过表达C/EBPβ可降低细胞对顺铂的敏感性，抑制C/EBPβ表达则增加细胞对顺铂的敏感性(图7c-7i)。
实施例2C/EBPβ对铂类耐药的促进作用是由DOT1L所介导的，C/EBP β-DOT1L可作为分子靶向治疗中的新靶点。
1、C/EBPβ能够促进H3K79甲基化
采用H3K79甲基化抗体做ChIP-Sequencing分析，结果显示沉默C/EBPβ使C13*细胞的整体H3K79甲基化水平降低(图8a)。同时本发明用C/EBPβ抗体做ChIP-Sequencing鉴定了的C/EBPβ靶基因。C/EBPβ靶基因与沉默C/EBPβ后H3K79甲基化水平降低的基因有显著的关联性(图8b，8c)。由于H3K79甲基化增高促进基因表达(Nat Rev Mol Cell Biol.2005；6(11):838-49)，本发明采用RNA-Sequencing分析了C/EBPβ调控的基因(图8d-8f)。最后汇总分析了沉默C/EBPβ引起的H3K79甲基化改变和基因表达水平改变，鉴定了沉默C/EBPβ后数百个H3K79甲基化降低并且表达水平降低的C/EBPβ靶基因(图8g)，其中有9个(图8g中指出的)是卵巢癌中已知的铂类耐药基因，另有21个基因在功能上可能与铂类耐药有关(图8h)。
2、C/EBPβ调控DOT1L介导的H3K79甲基化
DOT1L是唯一已知的H3K79甲基转移酶，而C/EBPβ是一个没有酶活性的DNA结合蛋白(Genes Dev.2011；25(13):1345-58)。用DOT1L抗体(ab72454；购自Abcam)做ChIP-Sequencing鉴定了的DOT1L靶基因。C/EBPβ靶基因与DOT1L靶基因之间有极为显著的关联性(图9a)，并且许多C/EBPβ结合位点与DOT1L结合位点非常接近(图9b，9c)。免疫共沉淀实验证明C/EBPβ与DOT1L有直接的相互作用(图9d)；ChIP-reChIP实验证明C/EBPβ与DOT1L能相互作用并共同结合与靶基因(图9e)。进一步，沉默C/EBPβ可以降低DOT1L与靶基因的结合能力(采用DOT1L抗体做ChIP-Sequencing和ChIP-qPCR证明，图9f-9h)。与此相一致，沉默DOT1L可以消除C/EBPβ过表达对基因表达的促进作用。因此，C/EBPβ与DOT1L结合并增强其与DNA结合的能力，从而调控H3K79甲基化。
3、C/EBPβ介导的铂类耐药依赖于其调控H3K79的作用
采用shRNA(shDOT1L-1,5′-GAGTGTTATATTTGTGAAT-3′；shDOT1L-2,5′-CACCTCTGAACTTCAGAAT-3′)沉默肿瘤细胞中DOT1L表达：DOT1L shRNA能消除C/EBPβ过表达对OV2008细胞耐药的促进作用；相似的，当DOT1L被沉默时，沉默C/EBPβ不能进一步降低C13*细胞的铂类耐药性(图10a)。为了进一步明确DOT1L是否介导了C/EBPβ对耐药表型的作用，通过文献检索分析了C/EBPβ-DOT1L共同靶基因的下游功能，并且发现其中很多基因可能与铂类耐药有关。为了在卵巢癌模型中验证这点，本发明在SKOV3细胞系(购买自TCGA细胞库)中用shRNA逐个沉默相应基因的表达。除了9个已知的铂类耐药基因之外，鉴定出14个促进卵巢癌铂类耐药的新基因(图10b)。这23个基因可能通过多条途径促进铂类耐药，大致可以分为三个方面：1)促进药物转导，2)增强DNA损伤修复，和3)调节信号通路增强细胞存活能力。与此相一致，沉默C/EBPβ产生对JAK-STAT、PI3K-AKT和MAPK信号通路的广泛抑制(图10c)，沉默C/EBPβ或DOT1L也可以增强铂类药物引起的DNA损伤(碱性彗星实验，图10d)并提高细胞内药物的累积(罗丹明药物积累试验，图10e)。
DOT1L shRNA能消除C/EBPβ过表达对DNA损伤修复(图10d)、药物转导(图10e)和存活通路(图10f和10g)的促进作用。相似的，当DOT1L被沉默时，沉默C/EBPβ不能进一步降低DNA损伤修复(图10d)和药物转导能力(图10e)。这些结果证明C/EBPβ对铂类耐药的促进作用是由DOT1L所介导的。最后发现，相对于顺铂单药治疗，联合DOT1L抑制剂(SGC0946、EPZ004777)和顺铂可以明显延长小鼠的生存时间。
此外，C/EBPβ增强顺铂耐药的作用与BRCA介导的DNA损伤修复能力密切相关(图11)。除卵巢癌之外，BRCA通路突变在乳腺癌铂类耐药中也起到重要作用(Front Oncol.2018；5；8:16)，因此C/EBPβ在乳腺癌的铂类耐药中也可能存在很好的临床应用前景。
Claims (2)
1.C/EBPβ基因或者蛋白和DOT1L蛋白联合作为生物标志物在制备a）肿瘤耐药风险和患者预后的诊断试剂中的用途，或b）肿瘤患者预后的诊断试剂中的用途，所述的肿瘤为卵巢癌；
所述的卵巢癌为高级别浆液性卵巢癌；
所述的耐药为化疗药物耐药，所述化疗药物为铂类化疗药顺铂；
所述的预后与高级别浆液性卵巢癌患者的生存时间相关，所述生存时间为高级别浆液性卵巢癌患者1.8年较短的疾病无进展生存时间，高级别浆液性卵巢癌患者2.2年较短的总生存时间。
2.C/EBPβ蛋白和DOT1L蛋白联合在制备抗卵巢癌药物的筛选标记中的用途；所述的卵巢癌为高级别浆液性卵巢癌。
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