二甲双胍通过激活AMPK调控FBP1磷酸化逆转肝癌糖代谢重编程的机制研究

The abnormal changes of glucose metabolism (i.e. glucose metabolic reprogramming) in tumors play a key role in tumorigenesis and progression, and the mechanism of regulation and control has become a challenging issue in the field of tumor. Liver is the main organ of glucose metabolism. Patients with liver cancer always have abnormal glucose metabolism, but the pathogenesis is still unclear. AMP-activated protein kinase(AMPK)and fructose-1,6-biphosphatase 1(FBP1）were two important molecules in the field of cancer metabolism.Our preliminary studies found that compared with adjacent tissues, p-AMPK and FBP1 were faintly expressed in hepatocellular carcinoma tissues, which were closely related to the poor prognosis. Low expression of p-AMPK and FBP1 may be associated with the regulation of glucose metabolism in hepatocarcinoma cells. However, whether AMPK regulates FBP1 is involved in HCC glucose metabolic reprogramming has not been reported. In this project, we firstly study the role of AMPK and FBP1 in the regulation of glucose metabolism in HCC. Secondly, it will clarify whether AMPK regulates FBP1 by phosphorylation. Finally, whether the traditional hypoglycemic agent metformin may reverse the abnormal glucose metabolism of liver cancer through AMPK/FBP1 signaling pathway.The present study contributes to elucidating the molecular mechanism of glucose metabolism reprogramming and the mechanism of metformin against liver cancer, and providing theoretical basis for clinical treatment and potential new targets .

糖代谢异常改变（即糖代谢重编程）在肿瘤发生发展中发挥重要作用，其调控机制研究一直是肿瘤领域的难点。肝脏是糖代谢的主要器官，临床上常见肝癌患者伴有糖代谢异常，但其致病机制仍不清楚。腺苷酸活化蛋白激酶（AMPK）和1,6，二磷酸果糖激酶1（FBP1）是近年来肿瘤代谢研究的热点。我们的预实验发现：与癌旁组织比较，肝癌组织中磷酸化的AMPK（p-AMPK）和FBP1低表达，并与患者预后不良密切相关；p-AMPK和FBP1低表达可能与肝癌糖代谢重编程有关。然而AMPK是否调控FBP1参与肝癌糖代谢重编程尚未见报道。本项目拟首先分析AMPK和FBP1在肝癌糖代谢重编程中的作用；其次明确AMPK是否通过磷酸化调控FBP1；最后探讨传统降糖药物二甲双胍是否通过AMPK/FBP1信号通路逆转肝癌糖代谢异常。该研究有望阐明肝癌糖代谢重编程的分子机制及二甲双胍抗肝癌的机理，为临床治疗提供理论依据和潜在的新靶点。

糖代谢异常改变（即糖代谢重编程）在肿瘤发生发展中发挥重要作用，其调控机制研究一直是肿瘤领域的难点。肝脏是糖代谢的主要器官，临床上常见肝癌患者伴有糖代谢异常，但其致病机制仍不清楚。腺苷酸活化蛋白激酶（AMPK）和1,6，二磷酸果糖激酶1（FBP1）是近年来肿瘤代谢研究的热点。本项目前期研究发现：与癌旁组织比较，肝癌组织中磷酸化的AMPK（p-AMPK）和FBP1低表达，并与患者预后不良密切相关；p-AMPK和FBP1低表达可能与肝癌糖代谢重编程有关。然而AMPK是否调控FBP1参与肝癌糖代谢重编程尚未见报道。本项目本从肝癌细胞、肝癌裸鼠移植瘤模型等方面，探讨二甲双胍对体内外肝癌模型的干预作用，及药物对肝癌糖代谢重编程的调控机制。发现二甲双胍通过促进糖异生抑制肝癌细胞增殖；活化的AMPK通过诱导FBP1表达上调抑制肝癌细胞增殖。二甲双胍可能通过调控HIF-1α/PFKFB3/PFK1信号通路减弱肝癌细胞糖酵解，进而抑制肝癌细胞增殖；靶向HIF-1α/PFKFB3/PFK1途径对糖酵解通量的控制很重要，为寻找二甲双胍抗肝癌治疗的新靶点和分子机制提供理论依据。