Mutual Regulation of MiR-199a-5p and HIF-1α Modulates the Warburg Effect in Hepatocellular Carcinoma

The Warburg effect is one of the major metabolic changes of cancer cells, which characterized by high level of glycolysis even in the presence of oxygen. However, the role of microRNAs (miRNAs) in regulating the glycolytic switch in cancer cells has not been well explored. In this study, we demonstrated that miR-199a-5p acts as a suppressor of the Warburg effect in hepatocellular carcinoma (HCC). MiR-199a-5p directly targets the 3'-untranslated region (UTR) of hypoxia-inducible factor-1α (HIF-1α), thereby suppressing glucose uptake, lactate production, cell growth, and expression of HIF-1α downstream glycolytic genes of HCC cells. Moreover, under hypoxic conditions, the expression of miR-199a-5p is suppressed by the up-regulation of HIF-1α. Thus, mutual regulation between miR-199a-5p and HIF-1α forms a positive feedback loop to promote glycolysis in HCC cells. Furthermore, miR-199a-5p is down-regulated in human HCC tissues and its low-level expression is associated with a worse survival of patients with HCC. Our findings suggest that miR-199a-5p/HIF-1α axis is critical in the regulation of the Warburg effect and also implicate miR-199a-5p as a potential therapeutic target for HCC.