肝癌起始细胞具有干细胞样特征，可脱离免疫监视进展为肝癌，而其形成过程及免疫逃逸的具体机制尚未阐明。本课题组前期分析临床病例及对应病理标本发现，APOBEC3B（A3B）高表达与患者预后负相关，过表达AB可促进CD133+的肝癌干细胞形成，同时可抑制CXCL9、CLCL10等免疫逃逸相关趋化因子的表达，推测A3B可促进肝癌起始细胞的形成及免疫逃逸。本项目主要研究内容：（1）利用体内外诱导肿瘤干细胞形成的研究策略，系统阐述A3B参与PRC2复合物的组装介导肝细胞表观遗传修饰改变，促进去分化重编程形成肝癌起始细胞的分子机制；（2）探索A3B降低CXCL10，MHC-I类分子介导肝癌起始细胞免疫逃逸的分子机制；（3）设计、合成并评价基于A3B功能抑制的小分子先导化合物，用于HCC的早期预防与治疗。通过上述研究不仅阐明肝癌发生发展的关键分子事件，也为研发新型肝癌预防和治疗药物提供理论基础和实验依据。

Liver tumor initiating cell is stem-like cell that can escape from immune surveillance and progress into liver cancer. However, the mechanism of formation of tumor initiating cell and escaping of the cell from immune surveillance remains elusive. Based on analysis of clinical samples and comparison of corresponding pathologic specimen, our previous work has found that high expression of APOBEC3B is related to poor prognosis of liver cancer patients. We has also found that overexpression of APOBEC3B can promote formation of CD133+ liver cancer stem cell but meanwhile suppress expression of cytokines related to immune escape such as CXCL9 and CLCL10. It is speculated that APOBEC3B takes part in formation of liver tumor initiating cell and its immune escape. This project will focus on the following contents. (1)Systematically investigate the mechanism of how APOBEC3B promotes dedifferentiation of liver cell to become tumor initiating cell by taking part into liver cell epigenetic change mediated by PRC2 complex based on the strategies of inducing tumor stem cells ex vivo.(2) Clarify the molecular mechanism of how APOBEC3B induces immune escape of liver tumor initiating cell by suppressing expression of CXCL10 and MHC-I molecules.(3) Develop small molecular inhibitors of APOBEC3B based on the mechanism discovered in this project. In sum, this project will clarify key molecular event during liver cancer initiation to provide principle and experimental basis for establishment of new drugs for liver cancer treatment.