Stat3-mediated activation of microRNA-23a suppresses... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating Glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha

Wang, Bo1,2; Hsu, Shu-Hao1,2; Frankel, Wendy3; Ghoshal, Kalpana3,4,†; Jacob, Samson T.1,4,*,a

1_Department of Molecular and Cellular Biochemistry, College of Medicine, Ohio State University, Columbus, OH_

2_Molecular, Cellular and Developmental Biology Graduate Program, College of Medicine, Ohio State University, Columbus, OH_

3_Department of Pathology, College of Medicine, Ohio State University, Columbus, OH_

4_Comprehensive Cancer Center, College of Medicine, Ohio State University, Columbus, OH_

*Address reprint requests to: 646 Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210

†646C TMRF, 420 West 12th Avenue, Columbus, OH 43210

Email:[email protected]

Received 27 September 2011; Accepted 24 January 2012

Grant sponsor: National Cancer Institute; Grant Numbers: CA086978 DK088076.

Potential conflict of interest: Nothing to report.

a_fax: 614-688-5600_

Abstract

Considerable effort has been made in elucidating the mechanism and functional significance of high levels of aerobic glycolysis in cancer cells, commonly referred to as the Warburg effect. Here we investigated whether the gluconeogenic pathway is significantly modulated in hepatocarcinogenesis, resulting in altered levels of glucose homeostasis. To test this possibility, we used a mouse model (mice fed a choline-deficient diet) that develops nonalcoholic steatohepatitis (NASH), preneoplastic nodules, and hepatocellular carcinoma (HCC), along with human primary HCCs and HCC cells. This study demonstrated marked reduction in the expressions of G6pc, Pepck, and Fbp1 encoding the key gluconeogenic enzymes glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, fructose-1,6-phosphatase, respectively, and the transcription factor _Pgc-1_α in HCCs developed in the mouse model that correlated with reduction in serum glucose in tumor-bearing mice. The messenger RNA (mRNA) levels of these genes were also reduced by ≈80% in the majority of primary human HCCs compared with matching peritumoral livers. The expression of microRNA (miR)-23a, a candidate miR targeting _PGC-1_α and G6PC, was up-regulated in the mouse liver tumors as well as in primary human HCC. We confirmed _PGC-1_α and G6PC as direct targets of miR-23a and their expressions negatively correlated with miR-23a expression in human HCCs. G6PC expression also correlated with tumor grade in human primary HCCs. Finally, this study showed that the activation of interleukin (IL)-6-Stat3 signaling caused the up-regulation of miR-23a expression in HCC. Conclusion: Based on these data, we conclude that gluconeogenesis is severely compromised in HCC by IL6-Stat3-mediated activation of miR-23a, which directly targets _PGC-1_α and G6PC, leading to decreased glucose production. (HEPATOLOGY 2012;56:186–197)