持续性乙型肝炎病毒（HBV）感染引起的慢性活动性肝炎（CAH）是我国肝癌发生的主要危险因子，肝脏局部炎症微环境中活化枯否细胞（KCs）产生的IL-6和TNF-α在促进肝癌发生过程中发挥重要作用。已有研究证实IL-6/IL-6R/gp130/STAT3信号异常活化在肝癌发生过程中促进肿瘤形成，并且HBV感染可以促进肝实质细胞分泌IL-6。本申请项目以HBV全基因组及其各编码蛋白和人肝癌细胞及组织为研究对象，围绕HBV感染调控肝癌细胞表面IL-6受体包括IL-6R和gp130表达变化及功能意义展开，从病毒致癌机制和肿瘤糖生物学角度出发，研究持续性HBV感染改变肝癌细胞表面gp130蛋白表达的分子机制及功能意义，建立肝癌细胞膜表面gp130分子N-糖基化修饰变化参与乙肝相关肝癌发生的分子调控和干预治疗模型，为开发针对N-糖基化修饰和gp130信号活化的肝癌分子靶向治疗临床研究和药物开发奠定基础。

Chronic active hepatitis (CAH) induced by persistent hepatitis B virus (HBV) infection remains the major etiologic risk factor for hepatocellular carcinoma (HCC) in China. Cytokine IL-6 and TNF-α secreted by activated Kuffer cells (KCs) in local liver inflammatory microenvironment play essential roles in HBV-associated hepatocarcinogenesis. Previous studies have shown that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females and obesity-promoted HCC development attributes to hepatic inflammation and activation of the oncogenic transcriptional factor STAT3 due to enhanced production of the tumor promoting cytokines IL-6 and TNF-α. Recent investigations found that somatic gp130 activation due to in-frame deletions occurs in 60% of inflammatory hepatocellular adenomas (IHACs), whereas 12% of IHAC subsets lacking gp130 mutations harbor somatic STAT3 mutations. In another report, hepatitis B virus X protein (HBx) stimulates the production of IL-6 in a MyD88-dependent manner in parenchymal liver cells. This project proposal for grant application is designed to elucidate the regulatory effect and functional role of persistent HBV infection during HBV-associated hepatocarcinogenesis on the expression of IL-6 receptor complex including IL-6R and gp130 in hepatoma cells using plasmids containing HBV genome or various HBV encoded gene and human hepatoma cells and tumor tissues. From the point of view in viral oncogenesis and cancer glycobiology, our present research project will focus on the molecular mechanism and functional significance for N-glycosylation-mediated alteration of membrane gp130 protein endocytosis and stability conferred by HBx expression due to persistent HBV infection, and will establish a model of molecular regulation and therapeutic intervention of gp130 N-glycosylation change on hepatoma cells membrane during HBV-associated hepatocarcinogenesis, which paves the way to clinical investigation and drug discovery based on molecular therapy targeting aberrant N-glycosylation and gp130 signal activation in liver cancer patients with chronic hepatitis B.