胰岛素经SREBP1/HDGF蛋白质复合体重编程脂代谢诱发肝癌的机制和意义

Diabetes is one of the most important risk factors of hepatocellular carcinoma (HCC). However the underlying mechanisms and coping strategies are still unclear. Deregulated lipid metabolism in liver is the common pathophysiological feature of diabetes and HCC. Abnormal in SREBP1 (Sterol regulatory element-binding protein 1)-mediated de novo lipogenesis is the pivotal mechanism involved in dysregulated lipid metabolism. Here we found that the accumulation of lipid in liver was mainly caused by SREBP1 activation upon stimulation by insulin in diabetes. In the meantime, insulin reprogrammed lipid metabolism via the complex of SREBP1 and HDGF (Hepatoma-derived growth factor). Furthermore, SREBP1 expression promoted tumorigenesis of HCC in vivo. Higher levels of SREBP1 predicted poor prognosis of patients with HCC. Therefore, we hypothesize that SREBP1 might play key roles in diabetes-related HCC. And lipid metabolism would be reprogrammed by SREBP1/HDGF complex upon stimulation by insulin. Proteomics, metabolomics, molecular targeted drugs, molecular imaging and other methods will be used in this study. The specific aim of our research is to unravel the mechanisms involved in SREBP1/HDGF complex reprogramming lipid metabolism, evaluate the effects of drugs targeting SREBP1/HDGF complex on treating diabetes-related HCC and evaluate the values of tracing agent in early diagnosis of diabetes-related HCC via targeting SREBP1/HDGF complex and lipid metabolism. Our work might provide a novel idea for personalized medicine for HCC.

糖尿病是肝癌的重要危险因素，但其致病机制和应对策略仍不明确。脂代谢紊乱是糖尿病和肝癌共同的病理生理特征，研究表明固醇调节元件结合蛋白1（SREBP1）功能异常是脂代谢紊乱的主要原因。我们发现胰岛素既可以通过SREBP1蛋白质磷酸化引起糖尿病性脂肪肝，又可以通过SREBP1/HDGF蛋白质复合体重编程肝癌细胞脂代谢，另外SREBP1又是肝癌驱动基因和预后危险因子。故研究假设SREBP1是衔接糖尿病和肝癌的重要桥梁，SREBP1/HDGF复合体对脂代谢的调节是糖尿病诱发肝癌的关键机制。本研究拟应用蛋白组学、代谢组学、分子靶向治疗和分子影像学等手段，阐明胰岛素经SREBP1/HDGF复合体重编程脂代谢诱发肝癌的机制；评估SREBP1/HDGF复合体靶向策略对肝癌的治疗价值；评估SREBP1/HDGF复合体及脂代谢显像策略对肝癌的诊断价值，为肝癌个体化诊疗提供新思路和新方法。

本课题在国家自然科学基金的支持下，系统研究了糖脂代谢重编程与肿瘤发生发展的关系。脂代谢方面研究发现SREBP1-Transgelin2信号轴通过对脂质代谢的调节成为衔接糖尿病和肿瘤发生的机制；靶向SREBP1抑制剂能通过MARVELD1蛋白调节细胞膜流动性及EGFR通路的化；SREBP下游基因ACLY可促进肿瘤细胞的转移；而SREBP1和PKM2的结合则是系统调节糖脂代谢重编程的重要机制；糖酵解限速酶PFKFB3通过直接结合CDK4影响靶向CDK4的疗效；而S6K2激酶通过调节PKM基因的选择性表达从而驱动肿瘤糖酵解代谢途径。研究为靶向肿瘤代谢干预肿瘤发生发展提供了关键靶点和理论基础。研究为靶向肿瘤代谢干预肿瘤发生发展提供了关键靶点和理论基础。发表标注本项目的SCI论文7篇，论文发表在Oncogene和JCB杂志。分别邀请了鲁汶大学的倪以成教授、爱因斯坦医学院的Fajun Yang等专家来华进行学术交流，扩大了本学科在国内外的影响力。项目的进展顺利，完成了既定的研究目标。