Hippo信号通路是近期肿瘤学及肿瘤免疫学的研究热点之一，其下游调控因子YAP转录活性的增强与肝癌的发生及免疫抑制息息相关。我们前期工作证明经典抗炎因子前列腺素E2（PGE2）IV型受体EP4可通过下游结合G蛋白Giα3抑制腺苷酸环化酶活性，下调PKA/LATs/YAP级联磷酸化途径增加YAP/TAZ的核转位，促进下游肿瘤相关基因的表达，导致肝癌发生。同时，Giα3介导的肿瘤细胞PGE2分泌，通过类似通路促进调节性T细胞（Treg）分化，诱导免疫抑制。因此，本课题将基于大量人肝癌组织，系统结合组织特异性相关基因敲除动物的肝癌模型，研究PGE2 /EP4/ Giα3通路在肝癌发生及免疫抑制中的具体作用，结合体外细胞模型阐明调控机制，并将相关机制应用于实验性肝癌治疗动物模型。为建立基于PGE2 /EP4/ Giα3通路的肝癌及肿瘤免疫治疗新方案奠定理论基础。

Hippo signaling pathway is one of the hot issues in both oncology and tumor immunology, the activation of its downstream YAP is seriously related to both hepatocarcinogenesis and immunosuppression. Our preliminary data indicated that Giα3 can promote hepatocarcinogenesis by downregulating PKA/LATs/YAP phosphorylation cascade and increasing YAP/TAZ nuclear trans-localization in a Prostaglandin E2/ EP4 dependent manner. Meanwhile, Giα3 related PGE2 secretion can also promote immunosuppression by increasing Treg cell differentiation via similar signaling pathway. Therefore, we proposed to explore the roles of PGE2/EP4/Giα3 in hepatocarcinogenesis and immunosuppression by systematic study on amount of human samples and spontaneous mice HCC model using tissue-specific gene Knockout mice. Moreover, the detailed regulatory mechanism will be applied to therapeutic mice HCC model. Our study will lay theoretical foundation for developing PGE2 /EP4/ Giα3 based therapeutic strategies for liver cancer.