cGAS是2013年初首次报道的新型DNA感受器，是新近国际科技前沿的研究热点。但是cGAS在肝癌中的作用尚不清楚。我们在前期研究中发现cGAS在肝癌中的表达显著下调和缺失，进一步研究发现cGAS能够抑制AKT-mTORC1信号通路，对肝癌具有显著的抑癌效应和增加索拉菲尼的治疗敏感度的效应。结构分析发现cGAS具有典型的ITIM基序，并能对SHP1进行同源性募集结合。由此我们提出假说，cGAS通过ITIM-SHP1轴抑制肝癌中的AKT-mTORC1通路，进而发挥抑癌效应和增强索拉菲尼的治疗效应。我们拟在本项目中通过细胞模型、动物模型和临床研究这一完整的研究体系，对于cGAS在肝癌中的作用效应及其对索拉菲尼治疗反应的调控效应进行研究，并探索基于cGAS对肝癌进行分子分型的可能性。该研究将为阐明肝癌的发生进展机制和对其进行分子靶向逆转奠定基础。

cGAS is a new type of DNA sensor and an important innate immune molecule, which was discovered and reported for the first time in the year of 2013. It has remained a research hot point in the field of innate immunity since its discovery. Because of the essential close relationship between the innate immunity and carcinogenesis, the role of cGAS in cancer has attracted more and more attention in recent years. However the role of cGAS in hepatocellular carcinoma(HCC) remained to be clarified. We carried out the research of cGAS in HCC for the first time and our data showed that expression of cGAS was significantly decreased in HCC tissues compared with corresponding distal non-cancerous liver tissues. Furthermore we verified that cGAS could inhibit the malignant behaviors of HCC and increase the response to sorafenib treatment. Molecular mechanism investigation showed that cGAS could inhibit the signaling of AKT-mTORC1 pathway and we verified that cGAS could recruit and bind with SHP1 via its ITIM motif. Thus we propose our hypothesis that cGAS could negatively regulate AKT-mTORC1 pathway via ITIM-SHP1 aixs, which further inhibit the malignant behaviors of HCC and increase the response to sorafenib treatment. In this study, we are going to study the role the cGAS in HCC in an integrate investigation system including cellular model, animal model and clinical investigation. We are going to study the molecular mechanism involved in the tumor suppressor function and responses to sorafenib treatment in HCC. This study could provide the basis to clarify the carcinogenesis of HCC and provide a novel target for its novel manipulation strategy.