Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People's Republic of China.
Department of Gastroenterology, the Fifth People's Hospital of Chengdu, Chengdu, Sichuan, 611130, People's Republic of China.
Cell Death Dis. 2018 Feb 15;9(3):264. doi: 10.1038/s41419-018-0308-4.
Metformin has been demonstrated to prevent hepatocellular carcinoma (HCC). Metformin acts mainly by phosphorylation of AMPK. However, the phosphorylation status of AMPK and its role in the prediction and prevention of HCC in cirrhotic patients remains unclear. The phosphorylation status of AMPK (Thr172) was determined by immunostaining in tissue microarrays of 426 cirrhotic liver tissues. Low expression of p-AMPK was observed in 94 (22.1%) cases. The median follow-up time was 87 months. HCC occurrence probability at 1/3/5/10 years after Hassab procedure was 3.1/9.6/13.8/30.6% in patients with p-AMPK low expression and 0/0.3/0.3/8% in patients with p-AMPK high expression, respectively. HCC occurrence risk was significantly higher in patients with p-AMPK low expression in univariable analysis (HR, 6.25; 95% CI: 3.36-11.60; P < 0.001) and multivariable analysis (HR, 6.0; 95% CI: 3.24-11.10; P < 0.001). An independent external cohort validated the significance of p-AMPK low expression. In addition, in vivo experiments demonstrated that AMPK activation status was negatively related to HCC occurrence and blocking autophagy by chloroquine counteracted the protective effect of AMPK phosphorylation. These results present novel insight into a critical predictive role of AMPK activation in hepatocarcinogenesis and AMPK activation seems to be a potential target for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.
二甲双胍已被证明可预防肝细胞癌（HCC）。二甲双胍的作用主要通过 AMPK 的磷酸化来实现。然而，在肝硬化患者中，AMPK 的磷酸化状态及其在 HCC 预测和预防中的作用尚不清楚。通过对 426 例肝硬化组织的组织微阵列进行免疫染色，确定 AMPK 的磷酸化状态（Thr172）。在 94 例（22.1%）病例中观察到 p-AMPK 表达水平低。中位随访时间为 87 个月。Hassab 手术后 1/3/5/10 年 HCC 发生概率在 p-AMPK 低表达患者中分别为 3.1/9.6/13.8/30.6%，在 p-AMPK 高表达患者中分别为 0/0.3/0.3/8%。在单变量分析中，p-AMPK 低表达患者 HCC 发生风险显著更高（HR，6.25；95%CI：3.36-11.60；P<0.001）和多变量分析（HR，6.0；95%CI：3.24-11.10；P<0.001）。一个独立的外部队列验证了 p-AMPK 低表达的重要性。此外，体内实验表明，AMPK 激活状态与 HCC 发生呈负相关，用氯喹阻断自噬可抵消 AMPK 磷酸化的保护作用。这些结果为 AMPK 激活在肝癌发生中的关键预测作用提供了新的见解，并且 AMPK 激活似乎是预防肝硬化患者肝细胞癌的潜在靶点。
