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. 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.
Highlights
Until recently, little effort has been made to understand the significance of Otto Warburg’s pioneering demonstration more than 8 decades ago that proliferating cancer cells metabolize8–10-fold more glucose to lactic acid than corresponding normal tissues under aerobic conditions [1]
Based on these data, we conclude that gluconeogenesis is severely compromised in hepatocellular carcinoma (HCC) by IL6-Stat3-mediated activation of miR-23a which directly targets PGC-1α and G6PC, leading to decreased glucose production
The predominance of aerobic glycolysis characteristic of most cancer cells facilitates conversion of pyruvate produced during glycolysis to lactate, which is secreted into the blood instead of oxidation to completion [2,3,4]
Summary
Little effort has been made to understand the significance of Otto Warburg’s pioneering demonstration more than 8 decades ago that proliferating cancer cells metabolize. While the conversion of pyruvate to lactate results in the recovery of NAD+ required for the maintenance of glycolysis and for continued cell proliferation in vivo [8], this process is energetically inefficient, producing just two out of 36 ATP molecules for each mole of glucose expended It is not known how such a dramatic shift in energy metabolism occurs and how this altered metabolism results in cancer phenotype. A suitable mouse model for HCC is available, which can induce liver tumors by feeding choline deficient and amino acid defined (CDAA) diet in the absence of any exogenous chemicals or virus [10] Tumorigenesis in this model involves steatosis, inflammation, fibrosis and insulin resistance that are the hallmarks of human HCC [11,12]. We explored the molecular mechanisms underlying the suppression of these enzymes and probable functional significance of this observation
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