肝脏枯否细胞FcγRIIB受体介导慢性非可控炎症促进肝癌起始细胞形成的信号网络研究

大量流行病学研究表明，肝癌与慢性非可控炎症密切相关，其关键调控机制未明。本课题组前期研究发现，肝脏枯否细胞FcγRIIB条件敲除小鼠DEN化学诱导肝癌与野生型小鼠相比，肝癌起始细胞数量增多，肝癌发生率增高，且可显著促进肝脏LTs表达，提示肝脏枯否细胞FcγRIIB功能降低与肝癌发生密切相关。本项目拟进一步研究：（1）肝细胞受到应激损伤后如何抑制枯否细胞FcγRIIB 功能；(2) 枯否细胞FcγRIIB调控肝脏干细胞LTs表达及其功能的机制；（3）LTs信号系统是否能通过激活APOBEC3B诱导肝脏干细胞基因突变促进肝癌起始细胞形成。本项目将从分子、细胞、动物模型和临床病例等多个水平，阐明枯否细胞 FcγRIIB在慢性非可控炎症中如何促进肝癌起始细胞形成，并为开发基于新靶点的肝癌防治新药奠定基础。

It is demonstrated by epidemiology that hepatocellular carcinoma（HCC）is closely related to non-resolving inflammation. However, the mechanism remains elusive. Our previous work showed that mice with conditional knockout of Kuffer cell FcγRIIB developed more HCC progenitor cells(HcPCs) and liver tumors compared to wild type mice. Meanwhile, we found that higher LTs level in FcγRIIB knockout mice compared to wild type mice, which demonstrated the possibility that Kuffer cell FcγRIIB is closely related to HCC carcinogenesis. This project will focus on the following contents:(1) To investigate how damaged liver cells encountered with stress suppress the function of Kuffer cell FcγRIIB(2) To investigate the mechanism of how Kuffer cells FcγRIIB regulate LTs of liver stem cell(3) To investigate if LTs signaling could promote emergence of tumor initiating cell by enhancing gene mutation of liver stem cell through stimulating APOBEC3B. In sum, we will clarify the mechanism by which Kuffer cell FcγRIIB deficiency promotes emergence of tumor initiating cell during non-resolving inflammation on molecular, cellular, animal and clinical sample levels, and provide evidence for new drugs for HCC treatment based on new targets.