甘氨酸乙酰基转移酶表达下调通过ACSL和p38MAPK/PPARα信号轴 介导脂质代谢重编程促进肝细胞癌侵袭转移的机制研究

肝癌具有高度侵袭性，手术切除率低，易复发转移，预后差。研究表明，脂质代谢的异常改变与肝癌侵袭转移密切相关，但具体机制有待阐明。我们前期通过代谢组学分析发现，苯甲基氨基乙酸及其调控酶GLYAT在癌旁肝组织、肝癌组织以及门静脉癌栓组织中表达逐渐降低，且表达水平与肿瘤分期、术后复发和生存率显著相关，提示GLYAT低表达可促进肝癌的侵袭转移。进一步实验发现，GLYAT下调可促进胞内脂滴分解和脂肪酸氧化利用，增强肝癌细胞迁移和侵袭能力；GLYAT还可与脂代谢关键酶ACSL以及p38MAPK通路相互作用来调控脂代谢模式转换。我们推测GLYAT下调可能通过ACSL和p38MAPK通路介导脂质代谢重编程，从而促进肝癌的侵袭转移。本课题拟从临床标本、动物模型和肝癌细胞等多层面阐明GLYAT在肝癌侵袭转移中的作用，探讨其介导脂代谢重编程的作用方式和调控机制，从脂质代谢角度为肝癌术后抗复发转移提供新的靶点。

Hepatocellular carcinoma (HCC) is a highly invasive malignancy. The metastasis is the main cause for poor prognosis of HCC patients. It is well known that lipid metabolic reprogramming is closely related to the progression and metastasis of HCC, yet the molecular mechanism remains unclear. Our previous metabolomics research found that the content of Hippuric acid and its key regulatory enzyme Glycine N-acyltransferase (GLYAT) was significantly lower in portal vein tumor thrombus tissues than in their counterpart tumor or peritumoral tissues, and was correlated with the differentiation and prognosis of HCC. However, the underlying mechanisms are less investigated. Our preliminary study further revealed that the low expression of GLYAT can mediate lipid metabolism by reducing cytoplasmic lipid droplet abundance, stimulating fatty acid oxidation (FAO) and oxidative phosphorylation, thus promoting HCC invasion and metastasis. We also found that GLYAT can drive this lipid metabolic reprogramming via regulating acyl-CoA synthetase ligase (ACSL), the key enzyme of lipid droplet catabolism, and p38 MAPK/PPARα signal pathway. Therefore, we propose the following hypothesis that the reprogrammed lipid metabolic patterns driven by down-regulation of GLYAT can promote tumor metastasis of HCC by interacting with ACSL and p38 MAPK/PPARα signal pathway. This project is aimed to clearly elucidate the functional role of GLYAT in the HCC invasion and metastasis process, as well as the detailed molecular mechanisms underlying GLYAT-driven lipid metabolic reprogramming, through multiple levels of “molecules, cell, animals, and then patients ”. Its completion will shed great light on the molecular regulatory mechanisms of GLYAT in HCC invasion and metastasis, and also provide novel potential therapeutic targets for HCC management from the perspective of lipid metabolism.