从细胞代谢失衡角度研究肝细胞癌发生，对治疗和预防肝细胞癌具有重要的指导意义。香叶基香叶基二磷酸合成酶（GGPPS）是甲羟戊酸途径中的一个重要分支酶，能通过异戊二烯化修饰Ras等多种小G蛋白广泛参与糖尿病、心衰等疾病的发生，但有关GGPPS调控细胞代谢导致肝细胞癌发生的机制尚无研究。我们发现：在肝细胞癌病人以及肝细胞癌小鼠动物模型的肿瘤组织中，GGPPS显著性高表达；特异性在小鼠肝脏中敲除GGPPS会加速二乙基亚硝胺诱导的肝细胞癌发生；缺失GGPPS会显著改变糖酵解及磷酸戊糖途径相关限速酶如G6PDH的表达水平，促进其代谢终产物的增加；靶向抑制磷酸戊糖代谢能拮抗缺失GGPPS导致的肿瘤早发表型，提示敲除GGPPS可能通过引起肝脏葡萄糖代谢失衡，促进磷酸戊糖途径调控肝细胞癌的发生。本课题将从分子、细胞、组织和个体水平系统研究GGPPS调节细胞内磷酸戊糖途径导致肝细胞癌发生的分子机制。

Research of the tumor metabolic regulation is important for the treatment and prevention of HCC. Geranylgeranyl diphosphate synthase (GGPPS) is a branch-point enzyme in mevalonate pathway and regulates various diseases (including type 2 diabetes and heart failure) through protein prenylation of small GTPasee, however whether GGPPS reprogrammed cell metabolism and subsequent HCC is still unknown. Previously we found that GGPPS was highly expressed in tumor tissue of HCC patients and mouse models. Liver-specific GGPPS knockout mice directly demonstrated that GGPPS-deficiency accelerated DEN-induced HCC development. Further study pointed out that lacking of GGPPS results in aberrant glycolysis and expression of pentose phosphate pathway-related enzymes. Moreover, treatment of the inhibitor of pentose phosphate pathway can suppress tumorigenesis of GGPPS knockout mice, suggesting GGPPS regulates HCC development via imbalanced glucose metabolism, particularly pentose phosphate pathway. In this study, systematic research will be used to explore mechanism of GGPPS-regulated pentose phosphate pathway in hepatocellular carcinogenesis.