持续性乙型肝炎病毒（HBV）感染引起的慢性活动性肝炎是我国肝细胞癌（HCC）发生的主要风险因子，建立持续性HBV 感染促进肝癌发生的分子调控和干预治疗模型是开发个体化分子靶向治疗药物的重要途径。C-X-C趋化因子受体4（CXCR4）信号活化在病毒感染、炎症反应和肿瘤发生中发挥重要作用。我们前期研究发现，肝癌患者肿瘤组织中CXCR4表达水平明显高于癌旁组织，并与TNM分期进展、患者生存和HBV感染显著相关。本申请项目拟在前期发现基础上，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，围绕持续性HBV感染促进肝癌发生发展的分子机制及其干预对策这一关键科学问题，分析持续性HBV感染状态下肝癌细胞膜表面趋化因子受体CXCR4表达变化的分子机制和功能意义，建立乙肝相关肝癌发生发展的分子调控、术后生存评估和干预治疗模型，为开发针对相应异常活化信号通路的肝癌个体化分子靶向治疗药物奠定基础。

Chronic active hepatitis (CAH) induced by persistent hepatitis B virus (HBV) infection remains the major etiologic risk factor for hepatocellular carcinoma (HCC) in China. Establishment of working model involving molecular regulation and therapeutic intervention for accelerated hepatocarcinogenesis due to persistent HBV infection is crucial for exploring personal molecular therapeutic strategies against HBV-associated HCC. C-X-C chemokine receptor 4 (CXCR4) relays pivotal signals for virus infection, inflammatory reaction and tumorigenesis. Our preliminary results showed increased CXCR4 levels in tumor tissues compared with peritumor tissues surgically resected from patients with HCC, which correlated with TNM progression, patient survival and HBV infection status. Based on these preliminary data, our current project proposal is designed to elucidate the regulatory effect and functional significance of persistent HBV infection on the membraneous CXCR4 expression levels in hepatoma cells during HBV-associated hepatocarcinogenesis. Plasmids containing endogeneous-driven HBV replicon or various HBV-encoded gene, human hepatoma cells and tumor specimens surgically resected from patients with HCC will be used to explore molecular mechanism and interventive stratigies for HBV-associated hepatocarcinogenesis involving CXCR4 signal activation in present study. From the point of view in viral oncogenesis, our present research project will focus on the molecular mechanism and functional significance for increased membraneous CXCR4 conferred by HBx expression due to persistent HBV infection, and will establish a working model of molecular regulation, postsurgical survival evaluation and therapeutic intervention of development and progression of HBV-associated HCC, which paves the way to clinical investigation and drug discovery based on molecular therapy targeting CXCR4 signal activation in liver cancer patients with chronic hepatitis B.