Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor, with a high mortality rate due to late symptom presentation and frequent tumor recurrences and metastasis. It is also a rapidly growing tumor supported by different metabolic mechanisms; nevertheless, the biological and molecular mechanisms involved in the metabolic reprogramming in HCC are unclear. In this study, we found that pyruvate kinase M2 (PKM2) was frequently over-expressed in human HCCs and its over-expression was associated with aggressive clinicopathological features and poor prognosis of HCC patients. Furthermore, knockdown of PKM2 suppressed aerobic glycolysis and cell proliferation in HCC cell lines in vitro. Importantly, knockdown of PKM2 hampered HCC growth in both subcutaneous injection and orthotopic liver implantation models, and reduced lung metastasis in vivo. Of significance, PKM2 over-expression in human HCCs was associated with a down-regulation of a liver-specific microRNA, miR-122. We further showed that miR-122 interacted with the 3UTR of the PKM2 gene. Re-expression of miR-122 in HCC cell lines reduced PKM2 expression, decreased glucose uptake in vitro, and suppressed HCC tumor growth in vivo. Our clinical data and functional studies have revealed a novel biological mechanism involved in HCC metabolic reprogramming.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most common fatal cancer worldwide [1]
PKL was the predominant form in the nontumorous liver tissues (NT) livers but its expression was unchanged in HCC tissues, implying that PKL might contribute to the normal metabolic functions in the livers while pyruvate kinase M2 (PKM2) might contribute to metabolic functions in HCC
Our study has provided evidence that PKM2 was over-expressed in human HCCs
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third most common fatal cancer worldwide [1]. Liver has many unique metabolic functions including gluconeogenesis, glycogen synthesis and storage, as well as blood glucose homeostasis. As HCC is highly proliferative, altered metabolic mechanisms are required to support its rapid demand for nutrients. Normal differentiated cells metabolize glucose through oxidative phosphorylation in the presence of oxygen and through glycolysis in the absence of oxygen. Despite a less energy-efficient metabolic route, cancer cells metabolize glucose through glycolysis even in the presence of oxygen and the phenomenon is called the Warburg Effect [2]. Increase of glucose uptake and production of lactate are typical signatures of the Warburg Effect [2]. Accumulating studies have shown that this preferential metabolic reprogramming to glycolysis channels glucose intermediates for the maximal biomolecule and anti-oxidant production [3]
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