Integrated analyses identify miR-34c-3p/MAGI3 axis for the Warburg metabolism in hepatocellular carcinoma

Activated oncogenes and loss of tumor suppressors contribute to reprogrammed energy metabolism and induce aerobic glycolysis, also known as Warburg effect. MicroRNAs are profoundly implicated in human malignancies by inhibiting translation of multiple mRNA targets. Using hepatocellular carcinoma (HCC) molecular profiles from The Cancer Genome Atlas (TCGA), we identified a handful of dysregulated microRNA in HCC glycolysis, especially miR-34c-3p. Antagonization of miR-34c-3p inhibited the lactate production, glucose consumption, extracellular acidification rate (ECAR), and aggressive proliferation in HCC cells. Hijacking glycolysis by 2-deoxy-d-glucose or galactose largely abrogated the suppressive effects of miR-34c-3p inhibition in HCC. Membrane associated guanylate kinase, WW, and PDZ domain containing 3 (MAGI3) is then identified as a direct functional target of miR-34c-3p in regulating HCC glycolysis and oncogenic activities. Mechanistically, MAGI3 physically interacted with β-catenin to regulate its transcriptional activity and c-Myc expression, which further facilitates the Warburg effect by increasing expression of glycolytic genes including HK2, PFKL, and LDHA. Moreover, overexpressed miR-34c-3p and reduced MAGI3 predicted poor clinical outcome and was closely associated with the maximum standard uptake value (SUVmax) in HCC patients who received preoperative ¹⁸ F-FDG PET/CT. Our findings elucidate critical several microRNAs implicated in HCC glycolysis and reveal a novel function of miR-34c-3p/MAGI3 axis in Warburg effect through regulating β-catenin activity.