自噬相关蛋白EI24调控食管鳞癌转移的新机制

在已结题国科金(No.81171923)的资助下，我们发现EI24是促癌分子miR-483-3p的靶基因，在食管鳞癌组织中低表达且与不良预后相关，EI24具有抑制肿瘤转移的作用并可激活自噬；还发现转录因子Sp1能调节EI24的表达并参与自噬调节，EI24的启动子区存在Sp1的作用位点；EI24能抑制食管鳞癌细胞中E3泛素连接酶TRIM28的表达。文献提示TRIM28与MAGE-A3形成的复合体可使AMPKα1泛素化并导致自噬抑制，反过来AMPKα1可能抑制Sp1的表达和功能。因此推测EI24可能通过自噬降解TRIM28调控AMPKα1/Sp1信号通路进而影响肿瘤转移。本课题将明确EI24调控AMPKα1/Sp1信号通路的具体机制，证明自噬在该机制中的作用，阐明EI24调控食管鳞癌转移的生物学功能，本课题将为AMPKα1/Sp1信号通路的调控提供新的见解，进一步为食管鳞癌的基因诊疗奠定基础。

Supported by the grant from the National Natural Science Foundation (No.81171923), we have previously found that EI24 was the direct target of miR-483-3p, which acted as an oncogene in esophageal squamous cell cancer (ESCC). EI24 expression is downregulated in ESCC tissues as compared with non-neoplastic tissues, and lower EI24 expression may predict worse survival of ESCC patients. Besides, up-regulation of EI24 can inhibit the metastasis of ESCC cells and induce autophagy. We have also found that the transcription factor Sp1 might regulate EI24 expression by binding to its promoter, and EI24 might inhibit the expression of TRIM28 in ESCC cells. According to the literature, TRIM28, one of E3 ubiquitin-ligase enzymes, can increase the ubiquitination of AMPK through the formation of complexes with MAGE-A3, thus inducing the inhibition of autophagy. In turn, AMPKα1 can inhibit the expression and function of Sp1. Thus we make a hypothesis that the EI24 might regulate AMPKα1/Sp1 signaling pathway via autophagy and inhibit the metastasis of ESCC. Our study aims to investigate the molecular mechanisms of EI24 in regulation of AMPKα1/Sp1 signaling pathway, verify the role of autophagy in this process, and elucidate the biological function of EI24 in regulating the metastasis of ESCC. Taken together, the study will provide a novel perspective for the regulation of AMPKα1/Sp1 signaling pathway, and new methods of gene diagnosis and gene therapy for ESCC.