STAT5A调控ACLY并介导自身乙酰化修饰影响肝癌转移的机制研究

微血管癌栓(MVI)是肝癌早期转移的表现，是影响早、中期肝癌术后复发及生存期的主要因素之一。积极探究其发生的具体机制并进行有效干预是改善肝癌患者预后的有效手段。申请人前期发现血脂异常的患者MVI发生率明显升高，而在肝脏特异性敲除STAT5A的小鼠基础上利用DEN诱导肝癌模型证实，STAT5A可以通过负调控脂代谢关键基因ACLY促进肝脏脂质沉积及肿瘤转移；与此同时，ACLY过表达能增强STAT5A的乙酰化从而调控其活性，而具体机制尚需进一步验证。因此，本课题拟1)探索STAT5A调控ACLY促进脂质代谢的分子机制；2)明确ACLY介导的STAT5A乙酰化对肝癌增殖、迁移功能的影响；3)揭示靶向ACLY的抑制剂对肝癌增殖、转移的影响。本研究有望为肝癌早期转移的诊断、相关药物靶点的临床转化提供新的方向和理论基础。

The prevalence of microvascular invasion (MVI) in specimens obtained from liver resection or transplantation is between15.0% and 57.1%.The presence of MVI is a histopathologic feature that indicates aggressive behavior of the HCC and predicts worse prognosisafter liver resection and transplantation. Exploring the mechanism of its occurrence and to carry out effective intervention is necessary for improving patients' survival..In this study, we first clinically found that patients with high TG and TC were associated with high incidence rate of MVI and poor prognosis. According to our STAT5A liver-specific knockout mice, we found that loss of STAT5A led tohigher liver cholesterol and triglyceride. Moreover, mice with STAT5A knockout showed higher incidence of vascular invasion. Besides, STAT5A negatively regulated the expression of ACLY, the key gene of lipid metabolism. At the same time, ACLY affected the acetylation of STAT5A to regulate its activity.Therefore, this project aims to 1) explore the specific mechanism of STAT5A regulating ACLY to promote lipid metabolism; 2) clarify the impact of ACLY-mediated STAT5A acetylation on the proliferation and migration of liver cancer; 3) reveal the role of inhibitors targeting ACLY on the proliferation of liver cancer .This study is expected to provide a new direction for the early diagnosis of liver cancer with MVI and provide a new drug target for HCC treatment.