Hepatitis C virus induced dysregulation of lipid metabolism and implications for HCC development (A02)

项目A02(Lohmann/Bartenschlager；丙型肝炎病毒诱导的脂代谢失调和对肝细胞癌发展的影响)解决了丙型肝炎的致癌前机制，特别强调了脂类动态平衡的紊乱。研究表明，丙型肝炎病毒感染改变了信号脂类的丰度和亚细胞分布，尤其是支持膜性丙型肝炎病毒复制细胞器生物发生的磷脂酸(PA)，促进选择性自噬、纤维化和肝细胞癌的发生。进一步研究表明，丙型肝炎病毒诱导的磷脂酰肌醇-4-激酶Ⅲα(PI4KA)具有促肿瘤活性。该项目现在将通过靶向蛋白质组学鉴定PA结合蛋白和鉴定PI4KA在侵袭和转移方面对细胞骨架的影响，从而确定丙型肝炎病毒诱导的脂毒性的肝癌致癌机制，从而为潜在的干预铺平道路。

Project A02 (Lohmann/Bartenschlager; Hepatitis C virus induced dysregulation of lipid metabolism and implications for HCC development) addresses the procarcinogenic mechanism of HCV with specific emphasis on the disturbance of lipid homeostasis. It has demonstrated that HCV infection alters the abundance and subcellular distribution of signalling lipids, especially phosphatidic acid (PA), which supports the biogenesis of membranous HCV replication organelles, promotes selective autophagy, fibrosis and HCC development. It has furthermore shown that HCV-induced Phosphatidylinositol-4-kinase IIIα (PI4KA) has protumorigenic activity. The project will now determine hepatocarcinogenic mechanisms of HCV-induced lipotoxicity by identifying PA-binding proteins by targeted proteomics and identifying the effects of PI4KA on the cytoskeleton with regard to invasiveness and metastasis, thus paving a way for potential intervention.