肿瘤相关成纤维母细胞血管紧张素I型受体通过Giα3关闭Hippo通路重塑肝癌免疫微环境的机制研究

免疫抑制性肿瘤微环境（TME）对肝细胞肝癌（HCC）的发生发展具有重要作用，而肝星状细胞来源的肿瘤相关成纤维母细胞（CAFs）是HCC肝癌TME的重要组分细胞。我们前期工作发现，CAFs中Giα3一方面招募骨髓来源的免疫抑制性细胞，一方面促进Treg细胞分化，促进肝癌的发生发展。在CAF中，Giα3蛋白可介导血管紧张素I型受体（AGTR1）信号通过调控E3泛素化酶NEDD4促进LATS1的降解，进而关闭Hippo通路，引起YAP1激活，引起基因表达谱的改变，导致免疫抑制性肝癌TME。因此，本课题将利用临床肝癌标本、细胞系、组织特异性敲除小鼠及原发性小鼠肝癌模型等，从体外和体内系统研究CAF中Ang II/AGTR1/Giα3通路靶向Hippo通路重塑肝脏TME的具体机制及其在肝癌发生中的作用，为肝癌的免疫治疗提供新的理论基础。

Tumor microenvironment plays a key role in hepatocellular carcinogenesis (HCC), in which the majority of cancer associated fibroblasts (CAFs) are derived from hepatic stellate cells (HSCs). Our preliminary results show that GIα3 in CAFs can recruit immunosuppressive cells from bone marrow and promote the differentiation of Treg cells leading to the initiation and development of HCC. Mechanistically, Giα3 induce LATS1 degradation induced by Angiotensin II (Ang II) and its receptor Angiotensin type I receptor (AGTR1) via ubiquitin proteasome pathway. Consequently, Hippo signaling is turned off and YAP1 activation resulting its downstream gene upregulation to reshape the heptic microenvironment induced an immunorepressive environment. In this project, we propose to investigate the role of Ang II/AGTR1/Giα3 pathway in pathogenesis of hepatocellular carcinoma (HCC) in CAFs focusing on the alteration of hepatic microenvironment, as improved understanding of these mechanisms will provide the theoretical basis for future improvement of HCC immunotherapy.