雄激素受体与环境因素在肝细胞癌发生中的交互作用

Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis in China. The incidence rate of HCC and its rank in cancer deaths in men are significantly higher than in women, which is attributed to gender related internal environmental differences to a great extent, in addition to the higher rate of HBV infection, smoking, alcohol and other environmental exposure in men than that in women. Androgen receptor (AR) enhances the transcription of HBV gene and promotes HBV replication by acting on androgen response elements (ARE) in EnhI region. HBV X protein (HBx) enhances the transcriptional activity of HBV by c-Src and GSK-3β. We speculate that this positive feedback mechanism is consecutively activated in men with HBV infection and promotes the development of HCC. However, so far there is no molecular epidemiological study with large sample to explore HCC associated AR gene markers and the interaction of AR with HBV virus, especially with HBx. On the base of our previous studies, a case-control study, including HBV positive HCC patients and HBV-infected subjects without HCC was designed to screen HCC related AR gene marker and environmental exposure through the detection of AR gene polymorphism and HBV virus characteristics, combined with epidemiological investigation, and investigate the interaction of AR gene with HBV virus among Han population, which would be of great economic and public health value for HCC prevention.

肝细胞癌（HCC）是我国常见恶性肿瘤，预后极差，男性发病率和在癌症死亡病例中排名均显著高于女性，除与男性HBV感染率，饮酒等环境暴露程度更高有关，不同性别所致内环境差异是重要影响因素。雄激素受体（AR）通过作用于HBV EnhI区的雄激素效应原件，增强HBV基因转录，促进HBV复制，而HBV X蛋白（HBx）通过c-Src和GSK-3β增强AR的转录活性，该正反馈机制在男性HBV感染者中持续激活，促进HCC发生发展。然而目前尚缺乏大样本分子流行病学研究探索与HCC发生相关的AR基因标志及AR与HBV，尤其是HBx间交互作用。本课题采用病例-对照研究方法，以HBV阳性HCC和非HCC HBV感染者为研究对象，通过检测AR基因多态性和HBV病毒特征，结合流行病学调查，筛选HCC相关AR基因标志和环境暴露，并研究其在HCC发生中的交互作用，对HCC病因预防具有重要经济和公共卫生价值。

肝细胞癌（HCC）是我国常见恶性肿瘤，预后极差，男性发病率和在癌症死亡排名均显著高于女性，除与男性HBV感染率，饮酒等环境暴露程度更高有关，不同性别所致内环境差异是重要影响因素。雄激素受体（AR）通过作用于HBVEnhI区的雄激素效应原件，增强HBV基因转录，促进HBV复制，而HBVX蛋白（HBx）通过c-Src和GSK-3β增强AR的转录活性，该正反馈机制在男性HBV感染者中持续激活，促进HCC发生发展。本项目采用病例-对照研究方法，以368例健康对照、323例HBV阳性HCC、284例非肝癌HBV感染者为研究对象，通过检测AR基因多态性和HBV病毒特征，结合流行病学调查，筛选HCC相关AR基因标志和环境暴露，并研究其在HCC发生中的交互作用。研究发现：①rs2234693C等位基因频率在HCC患者中低于非肝癌HBV感染者(OR=0.78，95%CI=0.62-0.99)，rs2228480AA基因型（vs.GG）增加ASCs与CHB患者进展为肝硬化的风险(OR=3.23，95%CI=1.26-8.28)，但是该基因型降低LC患者患癌的风险(OR=0.43，95%CI=0.19-0.96)；②在女性中，rs2234693C等位基因(CC+TC)（vs.TT）降低ASCs与CHB患者发展为肝硬化的风险(OR=0.34，95%CI=0.12-0.97)，在男性中，该等位基因降G低CHB与LC患者患癌风险(OR=0.63，95%CI=0.41-0.96)；③在HBVC型感染者中，经年龄与性别校正后，rs2228480A等位基因(AA+GA)携带者更易发展为肝硬化(AOR=2.20,95%CI=1.06-4.56)，但是经校正后差异无显著性；④⑤rs72627670CT基因型（VS.CC）与rs78445514等位基因G（VS.A）显著降低HBV感染者进展为HCC风险（OR=0.48,95%CI：0.23-0.99；OR=0.71,95%CI：0.51-0.99）；⑤单倍型分析发现，rs2234693C-rs2077647A-rs2228480G与rs2234693T -rs2077647G-rs22284G频率在HBV感染者中显著低于正常对照人群，提示携带该单倍型的人群感染HBV的风险可能更低。项目研究结果对筛选HCC高危感染者具有一定公共卫生价值。