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

Authors

  • Bo Wang,

    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
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  • Shu-Hao Hsu,

    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
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  • Wendy Frankel,

    1. Department of Pathology, College of Medicine, Ohio State University, Columbus, OH
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  • Kalpana Ghoshal,

    Corresponding author
    1. Department of Pathology, College of Medicine, Ohio State University, Columbus, OH
    2. Comprehensive Cancer Center, College of Medicine, Ohio State University, Columbus, OH
    • Kalpana Ghoshal, 646C TMRF, 420 West 12th Avenue, Columbus, OH 43210===

      Samson T. Jacob, 646 Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210===

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  • Samson T. Jacob

    Corresponding author
    1. Department of Molecular and Cellular Biochemistry, College of Medicine, Ohio State University, Columbus, OH
    2. Comprehensive Cancer Center, College of Medicine, Ohio State University, Columbus, OH
    • Kalpana Ghoshal, 646C TMRF, 420 West 12th Avenue, Columbus, OH 43210===

      Samson T. Jacob, 646 Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210===

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    • fax: 614-688-5600


  • Potential conflict of interest: Nothing to report.

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-1α 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-1α and G6PC, was up-regulated in the mouse liver tumors as well as in primary human HCC. We confirmed PGC-1α 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-1α and G6PC, leading to decreased glucose production. (HEPATOLOGY 2012;56:186–197)

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