核受体HNF4α通过调控雄激素受体表达促进去势抵抗性前列腺癌进展  

Nuclear receptor HNF4αpromotes castration-resistant prostate cancer via its regulation of androgen receptor expression

作　　者：王铸 张颖[1] 张建文[1] 邓琼[1] 梁辉[1] WANG Zhu;ZHANG Ying;ZHANG Jianwen;DENG Qiong;LIANG Hui(Urology Department,Affiliated Hospital of Longhua Shenzhen,Southern Medical University,Shenzhen 518109,Guangdong Province,China)

机构地区：[1]南方医科大学附属深圳龙华医院泌尿外科,广东深圳518109

出　　处：《中国癌症杂志》2021年第3期170-175,共6页China Oncology

基　　金：国家自然科学基金(81802566);深圳市科技计划项目(JCYJ20180228163919346)。

摘　　要：背景与目的:核受体肝细胞核因子4α(hepatocyte nuclear factor 4α,HNF4α)作为重要的转录因子,其在前列腺癌中的作用及调控机制尚不清楚。探讨HNF4α在前列腺癌去势抵抗进展中的作用及调控机制。方法:采用Oncomine数据库分析HNF4α在前列腺癌临床样本中的表达水平,并通过cBioPortal数据库分析HNF4α在不同类型前列腺癌中的表达特征及其对前列腺癌患者总生存率的影响。构建HNF4α慢病毒表达载体并转染到HEK-293细胞中用于慢病毒包装,上调LNCaP细胞中HNF4α表达,通过实时荧光定量聚合酶链反应(real-time fluorescence quantitative polymerase chain reaction,RTFQ-PCR)和蛋白质印迹法(Western blot)分析其对雄激素受体(androgen receptor,AR)表达水平的影响。通过萤光素酶报告基因实验分析HNF4α对AR表达调控的影响。结果:HNF4α基因在前列腺癌临床样本中表达上调,而且在去势抵抗性前列腺癌和神经内分泌前列腺癌样本中异常改变比例显著升高,与患者的总生存率呈负相关。HNF4α的外源性表达显著促进AR表达,并可能通过直接结合AR启动子的方式调控AR的基因转录过程。结论:核受体HNF4α在前列腺癌中表达上调并与前列腺癌恶性进展呈正相关,很可能通过直接靶向AR启动子促进其表达,HNF4α有望成为前列腺癌新的治疗靶点。Background and purpose:Nuclear receptor hepatocyte nuclear factor 4α(HNF4α)is a critical transcriptional factor,however,the functional and regulatory role of HNF4α in prostate cancer is not clear.The aim of this study was to investigate the mechanism of HNF4α involved in the development of castration-resistant prostate cancer.Methods:Oncomine analysis was used to characterize the expression level of HNF4α in clinical samples of prostate cancer.cBioPortal analysis was used to study the alteration of HNF4α in different subtypes of prostate cancer.The overall survival of prostate cancer patients with altered and unaltered HNF4α was also compared.The plenti-HNF4α vector was constructed and transfected into HEK-293 cells for lentivirus package.HNF4α was ectopically expressed in LNCaP cells,and its effect on androgen receptor(AR)expression level was analyzed by realtime fluorescence quantitative polymerase chain reaction(RTFQ-PCR)and Western blot.Luciferase reporter assay was performed to study the potential binding effect of HNF4α on AR promoter.Results:HNF4α was upregulated in clinical samples of prostate cancer,and the proportion of abnormal changes in castration-resistant prostate cancer and neuroendocrine prostate cancer samples was significantly increased,which was negatively correlated with the overall survival rate of patients.The exogenous upregulation of HNF4α significantly promoted the expression of AR,and was positively correlated with the expression of the luciferase reporter gene.Conclusion:HNF4α is upregulated in prostate cancer and likely promotes AR expression by directly targeting the AR promoter.HNF4α may serve as a new therapeutic target in prostate cancer.

关 键 词：核受体 肝细胞核因子4Α 前列腺癌 去势抵抗性前列腺癌 神经内分泌前列腺癌 

分 类 号：R737.25[医药卫生—肿瘤]