细胞衰老是细胞进入一种周期不可逆转的停滞而达到的相对稳定状态。诱导肿瘤细胞重新获得衰老特性是抑制肿瘤生长的重要途径之一。过去研究表明，治疗2型糖尿病的一线药物二甲双胍能抗肝癌，但其机制仍不清楚。本项目前期研究证实：低浓度二甲双胍抑制肝癌细胞增殖是通过促进肝癌细胞衰老实现的，同时发现AMPK活化促进SIRT1磷酸化，且AMPK和SIRT1存在相互作用。为了深入探讨AMPK是否通过直接磷酸化SIRT1介导肝癌细胞衰老，本项目拟首先分析AMPK是否通过磷酸化SIRT1调节其活性；其次检测SIRT1磷酸化对p53转录活性及肝癌细胞衰老的影响；最后通过肝癌裸鼠原位移植瘤模型和临床标本，探讨低浓度二甲双胍对肝癌细胞衰老的影响及其机制。该研究将为揭示二甲双胍抑制肝癌提供崭新的理论依据，并为利用AMPK/SIRT1信号途径作为诱导肝癌细胞衰老的新靶点提供重要的线索。

Cellular senescence is a relatively stable state of irreversible growth arrest. It is one of important approaches to inhibit tumor growth by inducing tumor cell senescence.Previous studies have showed that metformin, the first-line drug treating type 2 diabetes, can inhibit cell growth of Hepatocellular carcinoma, but its mechanism remains unclear. The preliminary data of this project indicated that low dose of metformin inhibited hepatoma cell proliferation by promoting hepatoma cell senescence. Moreover, activation of AMPK contributes to phosphorylation of SIRT1 and AMPK is found to interact with SIRT1. In order to further study if AMPK is involved in metformin-mediated cellular senescence via direct phosphorylation of SIRT1, the present project intends to observe whether AMPK regulates SIRT1 by phosphorylation, then followed by detecting the effect of SIRT1 phosphorylation on p53 transcriptional activity and hepatoma cell senescence. Finally, a nude mice model bearing hepatocellular carcinoma and clinical samples were used to observe the effect of low concentration of metformin on hepatoma cell senescence and to explore its underlying mechanism. The present work is expected to provide a new theoretical basis for metformin-induced retardation of hepatoma cell proliferation and to use the AMPK/SIRT1 signaling pathway as a new target for induction of hepatoma cell senescence.