一组新的乙肝病毒X基因的序列变异在原发性肝癌中的临床意义和功能研究

项目名称： 一组新的乙肝病毒X基因的序列变异在原发性肝癌中的临床意义和功能研究

项目编号： No.81502375

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 袁声贤

作者单位： 中国人民解放军第二军医大学

项目金额： 19万元

中文摘要： X蛋白是乙肝病毒感染导致原发性肝癌发生和发展的关键因子，编码X蛋白的基因序列具有一定的多态性，但是肝癌病人中X基因序列变异的特征、生物学意义和作用机制尚未被系统阐述。前期考察大规模临床样本中X基因的序列特征并筛选得到与肝癌病人较好预后密切相关的一组变异（X基因新亚型），我们由此推测这组基因变异可影响X蛋白的功效，是乙肝病毒致癌过程中重要的保护性因素。本研究拟从体内、外水平考察此组变异对X蛋白调控肿瘤细胞表型过程中所具效应的影响，利用高通量表达谱检测结合免疫共沉淀等手段阐明此组X基因变异对肝癌细胞下游通路的调控作用和分子机制，再利用临床队列考察X基因变异作为肝癌诊断标志物的价值。我们将首次报道能降低X蛋白致癌作用的一组基因变异，阐明其作用机制并探讨其临床价值，对进一步揭示X基因在肝癌中发挥作用的多样性，加强肝癌诊疗过程中乙肝病毒X基因型的重视程度具有重要意义。

中文关键词： C09_肝和肝内胆管肿瘤；乙型肝炎病毒；HBX基因；基因突变；分子标志物

英文摘要： X protein is the critical effector of hepatitis B virus in the carcinogenesis and development of liver cancer and amount of previous evidences have indicated the frequent variations in sequence of X gene. However, the exact charactors, biological functions and underlying mechanisms of X gene variation in hepatocellular carcinoma remain largely unclassifed. We previously explored the whole sequence of X gene in both tumoral and nontumoral tissues from a large cohort of HCC patients and found that a group of simulteneously occurred gene sequence variations (designated as novel X genotype) could predict the better prognosis of HCC patients after hepatectomy, which lead us to hypothesize that this novel X genotype might harbor biological significances and might pretect hepatitis B virus-infected liver from carcinogenesis and tumor progression. In this project, through comprasions of HCC cell phenotypes after transfection of wild type, novel genotype of X gene and scrambel control vectors, we aimed to illustrate the functional significance of the novel X genotype in the process of hepatocellular carcinoma advanced by X protein. The gene expression profiling would be applied to investigate the downstream signalling pathways correlated with the novel X genotype and immunoprecipitation assays would be used to explore the direct effector of X protein coded by the novel X genotype. Furthermore, we would investigate the potentially clinical value of the novel X genotype as a biomarker in liver cancer. Generally, this study would firstly uncover a group of variations in X gene with benefit for hepatocellular carcinoma when compared to wild type of X gene and clarity the underlying mechanisms, leading to more attention paid on X gene variations in diagonosis and therapy of hepatocellular carcinoma.

英文关键词： Hepatobiliary malignancy;Hepatitis B virus;HBX gene;Gene mutation;Biomarker