Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway.
The antidiabetic drug metformin has been shown to possess antitumor functions in many types of cancers. Although studies have revealed its beneficial effects on the prognosis of hepatocellular carcinoma (HCC), the detailed molecular mechanism underlying this event remains largely unknown. In this work, we showed that miR-23a was significantly induced upon metformin treatment; inhibition of miR-23a abrogated the proapoptotic effect of metformin in HepG2 cells. We next established forkhead box protein A1 (FOXA1) as the functional target of miR-23a, and silencing FOXA1 mimicked the effect of metformin. Moreover, the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of p53 were increased upon metformin treatment, and the inhibition of p53 abrogated the induction of miR-23a by metformin, suggesting that AMPK/p53 signaling axis is responsible for the induction of miR-23a by metformin. In summary, we unraveled a novel AMPK/p53/miR-23a/FOXA1 axis in the regulation of apoptosis in HCC, and the application of metformin could, therefore, be effective in the treatment of HCC.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Yunpeng
Y
Sun
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Chonglin
C
Tao
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Xiaming
X
Huang
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Han
H
He
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Hongqi
H
Shi
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Qiyu
Q
Zhang
Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Huanhuan
H
Wu
FOXA1; apoptosis; metformin; miR-23a; p53