识别原发性和耐受性前列腺癌中关键的转录因子

第I页识别原发性和耐受性前列腺癌中关键的转录因子摘要前列腺癌是世界高发性男性癌症，死亡率一直处于较高水平。然而，前列癌症的发生并不是单一因素作用的结果，通常是多个因子相互作用，相互影响的。针对早期前列腺癌(Primary),临床上采取内分泌治疗，用以抑制雄激素从而抑制癌症的进一步发展，但效果持续时间不长，经过一段时间治疗后，前列腺癌产生耐药性，发展成去势抵抗性前列腺癌(CRPC),在CRPC中，癌症的发展并不依赖雄激素受体。在该论文中，我们利用生物信息学分析方法，通过分析与比较Primary和CRPC病人高通量测序的RNA表达数据，筛选出CRPC中关键的转录因子ATF4和ETS2,对CRPC病人数据进行分类，利用基因富集分析方法，进一步探究关键转录因子潜在的功能。结果表明，PI3K-Akt信号通路和癌症的转录失调功能在AT℉4和ETS2高表达样本中被激活。此外，我们通过分析表观遗传修饰数据，进一步证明了CRPC中ATF4和ETS2启动子区域具有很强的H3K4me3和H3K27ac修饰信号，该信号与基因激活有关，有较弱的H3K27me3修饰信号，该信号与抑制基因有关，因此证明了ATF4和ETS2在CRPC中高度活跃，是CRPC的关键转录因子。通过高通量数据，对CRPC中关键转录因子进行系统分析，识别出AT℉4和ETS2关键转录因子及其潜在功能，为深入理解前列腺癌的发病机制，耐药机理提供了重要的方向，也为临床上治疗CPC提供一个新的思路关键词：前列腺癌；CRPC:生物信息：关键转录因子；ATF4:ETS2第Ⅱ页Identification of representative TFs in Primary and CastrationResistant Prostate Cancers(CRPC)Author:Zhang MengkeTutor:Chen YunlingAbstractProstate cancer is one of the most aggressive malignancy in the whole worldwith high mortality.Recent studies indicate that multiple factors can trigger toprostate cancer.In clinical,androgen-deprivation therapy is widely applied in primaryadenocarcinoma treatment,but a subset of patients can go to resistance and become acastration-resistant prostate cancer (CRPC),which shows Androgen Receptor (AR)independent status.In this study,we will apply bioinformatics analysis methods toidentify master transcription factors in CRPC and primary samples by using publishedCRPC and primary patient RNA-Seq data.The classification analysis based on theexpression of ATF4 and ETS2,and gene enrichment analysis further revealed thefunctions of master regulators,ATF4 and ETS2.Our results showed PI3K-Aktsignaling pathway and Transcriptional misregulation in cancer are high enriched inATF4 and ETS2 high samples.In addition,strong H3K4me3 and H3K27ac signal andweek H3K27me3 signal at ATF4 and ETS2 promoter regions further confirmed theactivated status of these two master regulators in CRPC samples.In summary,theidentification of ATF4 and ETS2 in CRPC through bioinformatics methods revealedthe potential mechanism between CRPC progression and master regulators,whichalso provide novel treatment direction in prostate cancer clinical research.Key words:Prostate cancer;CRPC;Bioinformatics;Master regulator;ATF4;ETS2第Ⅲ页目录t言.。1材料与方法32.1数据的获取…32.2方法.42结果与讨论0