癌蛋白HBXIP对肝癌细胞糖异生的影响及其分子机制研究

糖代谢重编程在癌症发生发展中发挥关键作用，成为国际上的研究热点。本课题组发现HBXIP可抑制肝癌细胞糖异生关键酶PEPCK1和G6Pase的作用。因此，提出“癌蛋白HBXIP可通过调节肝癌细胞糖异生导致糖代谢重编程”的假说。本申请拟以肝癌为研究对象，从分子、细胞、组织和动物模型等各个层面开展以下研究：（1）明确HBXIP通过抑制PEPCK1和G6Pase调节糖异生的作用；（2）在转录和转录后水平阐明HBXIP通过影响FoxO1和PGC-1α调控PEPCK1和G6Pase的分子机制；（3）揭示HBXIP介导的糖异生抑制导致糖代谢重编程及肝癌生长；（4）应用肝特异性HBXIP基因敲除小鼠研究肝脏中糖异生的变化及意义。本研究是肝癌糖代谢重编程分子机制研究领域的创新发现，将为肝癌的预防、治疗和新药开发等提供新的靶点，具有很好的应用前景。

Glycometabolism reprogramming plays an important role in cancer development and progression, becoming a research hotspot around the world. We have found that HBXIP can inhibit the function of key gluconeogenesis related enzymes PEPCK1 and G6Pase in hepatoma carcinoma cell. we address a novel hypothesis that HBXIP leads to glycometabolism reprogramming through regulating gluconeogenesis in hepatoma cells. This program will focus on liver cancer, conduct series of studies at molecular, cell, tissue and animal levels as follows: (1) explore the effect of HBXIP on gluconeogenesis via inhibiting PEPCK1 and G6Pase in hepatoma cells; (2) investigate the mechanism of HBXIP in regulation of PEPCK1 and G6Pase by FoxO1 and PGC-1α at the levels of transcription and post-transcription; (3) study the effect of HBXIP on promoting glycometabolism reprogramming and hepatocarcinogenesis via inhibiting gluconeogenesis; (4) demonstrate the significance of gluconeogenesis inhibition mediated by HBXIP by using liver of HBXIP-/- knockout mice. Our finding will provide new insights into the mechanism of glycometabolism reprogramming in liver cancer. Our data will provide new targets for the prevention, therapeutical strategy and drug discovery of liver cancer.