miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma.
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.
Department of Pharmacology, National University of Singapore, Singapore ; Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Angela M
AM
Liu
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Zhi
Z
Xu
Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Felix H
FH
Shek
Cancer Science Institute, National University of Singapore, Singapore.
Kwong-Fai
KF
Wong
Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Nikki P
NP
Lee
Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Ronnie T
RT
Poon
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Jinfei
J
Chen
Department of Pharmacology, National University of Singapore, Singapore ; Department of Surgery, National University Health System, Singapore ; Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China ; Cancer Science Institute, National University of Singapore, Singapore ; Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
John M
JM
Luk
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D006019:Glycolysis; D006801:Humans; D007124:Immunoenzyme Techniques; D019344:Lactic Acid / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097810:Thyroid Hormone-Binding Proteins
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D019344:Lactic Acid; D008565:Membrane Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C531907:MIRN122 microRNA, human