代谢重构在肝癌发生发展过程中起重要作用，但分子机制还不清楚。我们对配对临床肝癌样本进行基因表达芯片和代谢组学分析，发现肝癌肿瘤组织与正常组织相比糖酵解和磷酸戊糖途径代谢流增加，糖酵解途径关键代谢酶果糖1,6-二磷酸醛缩酶B（ALDOB）在癌组织中极大的下调，同时磷酸戊糖途径的限速酶G6PD显著上调；我们还发现ALDOB与G6PD相互作用抑制G6PD酶活及肿瘤细胞的增值与迁移；临床试验还显示ALDOB和G6PD的表达与肝癌预后生存相关。因此我们认为ALDOB调控着肝癌代谢重构并抑制肝癌的发生发展。在本项目中，我们将应用肝癌细胞、ALDOB肝特异敲除小鼠模型和临床实验等探讨ALDOB和G6PD如何介导肿瘤细胞代谢途径重构并促进肿瘤细胞的生长，以此揭示该基因和蛋白对肝癌细胞生长过程的代谢调控规律，为肝癌的临床诊断、药物靶点治疗和预后判断提供科学依据。

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and China accounts for > 50% of the newly diagnosed liver cancer cases. The unsatisfactory clinical prognosis of HCC has been largely attributed to a poor understanding of the underlying molecular mechanisms of HCC. Metabolic reprogramming has been regarded as the core hallmark of cancer but metabolic studies in HCC are surprisingly limited. Our gene expression microarray analysis found a significant downregulation of fructose-1,6-bisphosphate Aldolase B (ALDOB) in HCC tumor tissue comparing to adjacent normal tissues. ALDOB is a critical enzyme regulating glycolysis and gluconeogenesis; however, it is unknown whether loss of Aldob in HCC affords any metabolic advantages during the progression of HCC. WE HYPOTHESIZE THAT ALDOB ACTS AS A METABOLIC SWITCH COORDINATING GLYCOLYSIS AND PENTOSE PHOSPHATE PATHWAY DURING THE PROGRESSION OF HCC. We propose to investigate the molecular mechanism on how AldoB regulates metabolic reprogramming in HCC using metabolic flux analysis, cell and liver specific knockout of ALDOB mouse model as well as clinical samples. Our preliminary studies identified that expression patterns of ALDOB and glucose-6-phosphate dehydrogenase (G6PD) predicted the clinical outcome of HCC. Over-expression of ALDOB and G6PD knockdown significantly suppressesed tumor cell proliferation and migration in vitro and in vivo. Furthermore, ALDOB suppressed tumorigenesis by direct interaction with G6PD and inhibiting G6PD activity. Successful completion of this project will establish a critical role for ALDOB in metabolic reprogramming to sustain tumor cell rapid proliferation and survival, suggesting that targeting ALDOB and its interaction with G6PD might be a viable therapeutic strategy.