title: Switching of pyruvate kinase isoform L to M2 promotes metabolic reprogramming in hepatocarcinogenesis.
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.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Sandy Leung-Kuen
authors.initials: SL
authors.lastname: Au
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Aki Pui-Wah
authors.initials: AP
authors.lastname: Tse
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Iris Ming-Jing
authors.initials: IM
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Robin Kit-Ho
authors.initials: RK
authors.lastname: Lai
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: David Kung-Chun
authors.initials: DK
authors.lastname: Chiu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Larry Lai
authors.initials: LL
authors.lastname: Wei
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Dorothy Ngo-Yin
authors.initials: DN
authors.lastname: Fan
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Felice Ho-Ching
authors.initials: FH
authors.lastname: Tsang
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Regina Cheuk-Lam
authors.initials: RC
authors.lastname: Lo
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, HKSAR; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, HKSAR.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C531907:MIRN122 microRNA, human