乙型肝炎病毒的进化对肝细胞癌进展的作用

HBV相关的肝细胞癌（HCC）仍威胁着全球2.57亿慢乙肝患者。HBV的进化对临床策略有重要意义，然而与HCC的关联仍然未知。申请人前期发现HCC表型改变与限制HBV复制传播有关，可能是受到HBV进化的竞争压力的结果。由此申请人提出假说，HBV与HCC可能存在协同进化的关系。本研究拟通过HBV全长克隆测序和全外显子加转录组测序对肝癌切除术患者癌、癌旁非癌、癌远端非癌组织内的HBV进化及宿主细胞进化进行分析。通过进化的角度寻找HCC进展中HBV与宿主细胞的关键事件，用体外感染实验验证，确定HBV影响HCC发生的关键因素。本项目对HBV与HCC关系提出全新见解，帮助阐明HBV如何驱动HCC的发生，为临床防治HBV相关HCC寻找早期标志物与治疗靶标提供新思路。

HBV-related hepatocellular carcinoma (HCC) still threatens 257 million patients with CHB worldwide.The evolution of HBV has important implications for clinical strategies, yet the association with HCC remains unknown. The applicant's pre-basic finding that HCC phenotypic alterations are associated with limiting HBV replication propagation may be the result of competitive pressure from HBV evolution. This led the applicant to propose the hypothesis that there may be a co-evolutionary relationship between HBV and HCC. In this study, we propose to analyze HBV evolution and host cell evolution in tumor, adjacent non-tumor and distal non-tumor tissues of hepatocellular carcinoma resection patients by HBV full-length clone sequencing and whole-exome plus transcriptome sequencing to depict the evolution of HBV and host cells during the progression of HCC. The key events in HCC progression were searched for from an evolutionary perspective and validated by in vitro infection experiments to identify the key factors of HBV affecting HCC development. This project provides novel insights into the relationship between HBV and HCC, helping to elucidate how HBV drives HCC development and providing new ideas for finding early markers and therapeutic targets for clinical prevention and treatment of HBV-related HCC.