Abstract
In contrast to normal differentiated cells that depend on mitochondrial oxidative phosphorylation for energy production, cancer cells have evolved to utilize aerobic glycolysis (Warburg’s effect), with benefit of providing intermediates for biomass production. MicroRNA-122 (miR-122) is highly expressed in normal liver tissue regulating a wide variety of biological processes including cellular metabolism, but is reduced in hepatocellular carcinoma (HCC). Overexpression of miR-122 was shown to inhibit cancer cell proliferation, metastasis, and increase chemosensitivity, but its functions in cancer metabolism remains unknown. The present study aims to identify the miR-122 targeted genes and to investigate the associated regulatory mechanisms in HCC metabolism. We found the ectopic overexpression of miR-122 affected metabolic activities of HCC cells, evidenced by the reduced lactate production and increased oxygen consumption. Integrated gene expression analysis in a cohort of 94 HCC tissues revealed miR-122 level tightly associated with a battery of glycolytic genes, in which pyruvate kinase (PK) gene showed the strongest anti-correlation coefficient (Pearson r = −0.6938, p = <0.0001). In addition, reduced PK level was significantly associated with poor clinical outcomes of HCC patients. We found isoform M2 (PKM2) is the dominant form highly expressed in HCC and is a direct target of miR-122, as overexpression of miR-122 reduced both the mRNA and protein levels of PKM2, whereas PKM2 re-expression abrogated the miR-122-mediated glycolytic activities. The present study demonstrated the regulatory role of miR-122 on PKM2 in HCC, having an implication of therapeutic intervention targeting cancer metabolic pathways.
Highlights
Hepatocellular carcinoma (HCC) is a common malignant tumor
The present findings supported the role of miR-122 on reversing the aerobic glycolysis to normal physiologic oxidative phosphorylation in HCC cells
The connection between PKM2 and miR-122 was observed during differentiation process of human embryonic stem cell into hepatocytes [15]
Summary
Hepatocellular carcinoma (HCC) is a common malignant tumor. In 2008, there were over 700,000 new incidences diagnosed worldwide [1]. HCC patients usually have poor clinical outcome – only 5–9% of them survive five years or more. Liver transplantation, and radiofrequency ablation may provide cure for some early staged patients, but most patients are diagnosed at advanced stage given the asymptomatic nature of HCC. HCC is highly resistant to chemoregimens, many of the patients die from disease recurrence. MiRNA has emerged as an important class of gene regulator in HCC development, and the investigation of its relevant regulatory mechanisms might provide new targets for the therapeutic intervention
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