乙肝恶性转化过程中病毒变异与炎症网络的交互作用机制

项目名称： 乙肝恶性转化过程中病毒变异与炎症网络的交互作用机制

项目编号： No.91529305

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 曹广文

作者单位： 中国人民解放军第二军医大学

项目金额： 249万元

中文摘要： 乙肝病毒（HBV）变异和炎症调控网络与肝细胞癌（HCC）有显著关联，但尚不清楚两者协同促癌机制。本课题拟整合三个互补性课题的前期发现，结合HCC体细胞驱动变异调控网络，探索HBV变异和炎症调控网络协同促进HCC进化发育的分子机制。拟采用深度测序阐明体细胞驱动变异调控的关键信号通路与HBV变异在HCC再发异质性形成中的作用，补充和验证前期发现的四个主要信号通路；阐明炎症网络节点分子与HBV变异的交互作用与HCC发生和再发的关联性；确定四个主要信号通路和体细胞变异调控的新通路分子与HBV变异对HCC发生和预后的贡献；通过细胞、动物和HCC组织移植模型，阐明HBV变异对炎症信号网络的调控作用和炎症信号网络对HBV复制的调控作用，以及二者对HBV-HCC的促进作用及其分子机制。本课题对阐明HBV致癌机制，完善癌症进化发育学理论，发现HCC发生和预后标志及治疗靶标，对有效预防和治疗HCC有重要意义。

中文关键词： 乙肝病毒变异；炎症信号网络；肝细胞癌；整合

英文摘要： Hepatitis B virus (HBV) mutations and inflammation-regulating networks have been significantly associated with the development of hepatocellular carcinoma (HCC), respectively. However, their synergistic role on the promotion of HCC remains largely unknown. In this project, we aim to explore the synergistic roles of the HBV mutations and proinflammatory molecular networks on the promotion of HCC via integrating the findings of three previous projects with complementarity and the networks regulated by somatic “driving” mutations in HCC. We will carry out the following investigations in this project: 1. To clarify the roles of the HBV mutations and key signaling pathways regulated by deep sequencing-derived somatic “driving” mutations on the formation of heterogenicity in postoperative HCC recurrence, replenish and verify the roles of 4 key inflammatory signaling pathways identified in the 3 previous studies. 2. To elucidate the the interactions of inflammatory network nodule factors with the HBV mutations as well as their associations with HCC occurrence and recurrence. 3. To determine the etiological roles of previously identified signaling pathways, somatic mutations-regulated novel pathway molecules, and the HBV mutations on HCC occurrence and postoperative recurrence. 4. To determine the effect of HBV mutations on the regulation of proinflammatory signaling networks, the effect of proinflammatory signaling networks on the replication of HBV, and both in promoting the development of HCC and the mechanisms in cell models, animal models, and patient-derived xenograft models, consecutively. This integrative project will of great significance in elucidating the mechanism of HBV-induced hepatocarcinogenesis, enriching the theory of Cancer Evo-Dev, identifying novel surveillance and prognostic biomarkers as well as therapeutic targets to improve prediction, active prophylaxis, and targeted treatment for HBV-related HCC.

英文关键词： HBV mutations;inflammatory signaling network;hepatocellular carcinoma;integration