基于肿瘤微环境蛋白质组研究CYP2E1作为肝癌防治靶点的关键基础

肝癌发生发展与肿瘤微环境密切相关，蛋白质组学方法可有助于从肝癌微环境中发现新靶点及其作用机制。我们前期两个国自然基金项目发现，肝癌患者肿瘤微环境中CYP2E1活性明显增高并与生存期负相关，且动物CYP2E1先天活性与肝癌发生发展有因果关系。提示CYP2E1可能为肝癌防治的新靶点。. 本研究拟采用蛋白质组学方法，以CYP2E1特异性抑制剂和cyp2e1敲除鼠为实验工具，研究CYP2E1作为肝癌防治靶点的关键基础。探讨肝癌患者体内外CYP2E1活性改变，发现CYP2E1与肝癌发生的相关性；探讨肝癌患者肿瘤微环境蛋白质组改变，发现微环境中CYP2E1相关蛋白质组；分别探讨cyp2e1表达缺失和CYP2E1抑制剂对肝癌发生发展的影响，进一步验证和筛选CYP2E1相关蛋白质组，并发现其下游信号通路。以期在肿瘤蛋白质组微环境方面，阐明CYP2E1的促癌机制及其抑制剂的抗癌机制。

Hepatocellular carcinoma (HCC) is closely related to the tumor microenvironment, and the proteomics method can help to discover new targets and mechanism from the HCC microenvironment. Our previous two national natural science fund projects found that CYP2E1 activity in tumor microenvironment of HCC patients was significantly increased and negatively correlated with survival time, and the innate activity of CYP2E1 in animals had a causal relationship with the occurrence and development of HCC, suggesting that CYP2E1 might be a new target for prevention and treatment of HCC.. In this study, proteomics as method, CYP2E1 specific inhibitors and cyp2e1 knockout animals as experimental tools will be used to study the key basis of CYP2E1 as target for prevention and treatment of HCC. Changes of CYP2E1 activity in HCC patients in vivo and in vitro, and correlation between CYP2E1 and the development of HCC will be investigated. Changes of HCC tumor microenvironment proteome and CYP2E1-related proteome in tumor microenvironment will be discovered. Effect of CYP2E1 expression deletion and CYP2E1 inhibitor on the development of HCC will be evaluated, further to verify and screen the CYP2E1-related proteome and its downstream signaling pathway. The aim is to elucidate cancer-promoting mechanism of CYP2E1 and anticancer mechanism of its inhibitor in terms of tumor proteome microenvironment, so as to provide a new target for the prevention and treatment of HCC.