肝星状细胞通过线粒体代谢转变调控乳酸穿梭影响肝癌干细胞干性的机制研究

肝星状细胞（HSC）作为肝癌微环境中重要的间质细胞，在肝癌恶性进程中扮演重要角色。然而，HSC对于肝癌干细胞池的作用及调控机制尚不明确。申请人前期研究发现线粒体代谢转变在肿瘤的恶性转化及干细胞的自我更新中扮演重要角色，提示线粒体代谢模式可能影响肿瘤微环境中的细胞命运。进一步，申请人发现与肿瘤共培养后，HSC发生激活，伴随AMPK/PGC-1α信号通路介导的代谢模式转变，并通过增强肿瘤细胞的乳酸摄取，促进肝癌干性。本研究拟在前期基础上，系统检测肝癌微环境中HSC的代谢表型。利用有氧糖酵解抑制剂，研究HSC代谢模式与激活状态的关系，并明确代谢产物乳酸对肝癌干细胞的影响。最后通过激活AMPK/PGC-1α信号，探究在HSC线粒体代谢模式转变中的作用，阐明HSC通过乳酸穿梭影响肝癌干性的分子机制。通过以上研究，不仅增强对肿瘤微环境中代谢偶联的认识，也为研发新靶点降低肝癌恶性程度提供理论依据。

Hepatic stellate cells (HSCs), as important interstitial cells in liver cancer microenvironment, play an important role in the malignant process of liver cancer. However, the role of HSCs in hepatocellular carcinoma (HCC) stem cell pool and its regulatory mechanism is unclear. Previous studies by the applicant found that the metabolic shifts of mitochondria play an important role in the malignant transformation of tumors and the self-renewal of stem cells, suggesting that the mitochondrial metabolism mode might affect the cell fates in the tumor microenvironment. Furthermore, we found that after co-culture with the HCC cells, the HSCs were activated with the metabolic pattern change mediated by the AMPK/PGC-1α signaling pathway, meanwhile promoting the stemness of HCC by enhancing the lactate uptake by tumor cells. This study is intended to systematically detect the metabolic phenotype of HSCs in the liver cancer microenvironment on the basis of previous studies. With the use of inhibitors of aerobic glycolysis, we are going to explore the relationship between HSCs metabolic patterns and activation state, as well as the role of metabolites, lactic acid, in promoting stemness of HCC stem cells. Finally, we explored the mechanisms of AMPK / PGC-1α signaling pathway in HSCs mitochondrial metabolic shifts and elucidated the molecular mechanism by which HSC affects the stemness of HCC through lactic-acid shuttle. Taken together, these studies will not only enhance our understandings of the metabolic coupling in the cancer microenvironment, but also provide a theoretical basis for the developing a promising target to reduce the degree of malignancy of liver cancer.