FTCD调控肝癌代谢重编程的分子机制及生物学功能研究

肝癌是全球常见的恶性肿瘤之一，其早期诊断较难，进展迅速，目前有效的治疗药物非常有限。因此，深入挖掘肝癌发生发展的机制、探寻新的治疗靶点是肝癌研究领域的重点和难点。FTCD是肝肾特异性表达的双功能酶，目前尚不清楚FTCD在肝癌中的作用。我们前期利用高通量表达谱芯片筛选，发现FTCD在肝癌中表达下调，且与肝癌患者的不良预后相关。过表达FTCD可抑制肝癌细胞的克隆形成和增殖能力。全谱代谢组学检测分析，发现FTCD的表达变化可影响D-甘露糖及L-谷氨酰胺的合成或摄取。RNA-Seq高通量测序结果显示，敲除FTCD可激活肝癌中Wnt/β-catenin代谢相关通路。因此，我们推测FTCD在肝癌代谢重编过程中可能发挥重要的作用。本项目拟从细胞水平、多种动物肿瘤模型并结合临床样本系统地研究FTCD及其调控的代谢通路在肝癌进展中的作用。本项目有助于探索肝癌发生发展的机制，有望为肝癌治疗提供实验依据。

Liver cancer is one of the most common malignant tumors in the world. Early diagnosis of liver cancer is difficult and its progress is rapid. Effective therapeutic drugs currently are very limited. Therefore, it is the key and difficult point to investigate the mechanism for development and progression of liver cancer, and to explore the new therapeutic targets. FTCD is a liver and kidney-specific bifunctional enzyme. However, the function of FTCD in the development and progression of liver cancer is unknown. Our previous results of high-throughput expression profiling showed that FTCD expression was significantly down-regulated in HCC tissues and associated with prognosis of HCC patients. Overexpression of FTCD significantly inhibited the colony formation and growth of HCC cells. Untargeted metabolomics analysis also revealed that changes in the expression of FTCD could affect the synthesis or uptake of D-mannose and L-glutamine. In addition, high-throughput RNA-Seq results showed that knockout of FTCD activated Wnt/β-catenin signaling pathway, which is closely associated to tumor metabolism. Therefore, we speculate that FTCD may play an important role in the metabolic reprogramming of HCC. This project aims to study the function and metabolic regulation of FTCD in HCC progression using HCC cells, multiple mouse tumor models of HCC, and analysis for samples from HCC patients. Our project may help to explore the mechanism of HCC progression and provide evidences for HCC treatment.