Pyruvate kinase M2 promoted aerobic glycolysis and growth of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer which describes the malignancy derived from hepatocytes. HCC has a high mortality rate due to frequent tumor recurrence and metastasis, as well as late symptom presentation. HCC is one of the most rapidly growing tumors and its metabolic mechanisms significantly differ from normal liver; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are largely unknown. In this study, with isoform-specific primers, we found that pyruvate kinase M2 (PKM2) but not the other pyruvate kinase isoforms (PKM1, PKL, or PKR) was frequently over-expressed in human HCCs. HCC tissue micro-array also confirmed that PKM2 was over-expressed in 109 cases of human HCC. Over-expression of PKM2 was significantly correlated with aggressive clinicopathological features of HCC including tumor microsatellite formation, venous invasion, and absence of tumor encapsulation. Furthermore, over-expression of PKM2 in HCC was associated with increased tumor relapse, poorer overall and disease-free survivals in HCC patients. Knockdown of PKM2 profoundly reduced glucose uptake and lactate production and increased reactive oxygen species (ROS) accumulation in HCC cells in vitro. Knockdown of PKM2 not just suppressed cell proliferation in HCC cell lines in vitro, but also significantly hindered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced growth of lung metastatic lesions in vivo. Intriguingly, the expression of PKM2 was found to be inversely correlated with miR-122, a liver-specific microRNA that was frequently down-regulated in HCC. We further provided evidence that miR-122 interacted with the 3’UTR of the wildtype but not the mutated PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake and lactate production in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed an important regulatory pathway which involves miR-122/PKM2 in HCC metabolism.