title: Hepatitis B Virus Pre-S2 Mutant Induces Aerobic Glycolysis through Mammalian Target of Rapamycin Signal Cascade.
abstract: Hepatitis B virus (HBV) pre-S2 mutant can induce hepatocellular carcinoma (HCC) via the induction of endoplasmic reticulum stress to activate mammalian target of rapamycin (MTOR) signaling. The association of metabolic syndrome with HBV-related HCC raises the possibility that pre-S2 mutant-induced MTOR activation may drive the development of metabolic disorders to promote tumorigenesis in chronic HBV infection. To address this issue, glucose metabolism and gene expression profiles were analyzed in transgenic mice livers harboring pre-S2 mutant and in an in vitro culture system. The pre-S2 mutant transgenic HCCs showed glycogen depletion. The pre-S2 mutant initiated an MTOR-dependent glycolytic pathway, involving the eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), Yin Yang 1 (YY1), and myelocytomatosis oncogene (MYC) to activate the solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1), contributing to aberrant glucose uptake and lactate production at the advanced stage of pre-S2 mutant transgenic tumorigenesis. Such a glycolysis-associated MTOR signal cascade was validated in human HBV-related HCC tissues and shown to mediate the inhibitory effect of a model of combined resveratrol and silymarin product on tumor growth. Our results provide the mechanism of pre-S2 mutant-induced MTOR activation in the metabolic switch in HBV tumorigenesis. Chemoprevention can be designed along this line to prevent HCC development in high-risk HBV carriers.
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Chiao-Fang
authors.initials: CF
authors.lastname: Teng
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Hsieh
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Yih-Jyh
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University College of Medicine, Tainan, Taiwan.
authors.forename: Wenya
authors.initials: W
authors.lastname: Huang
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan; Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D006509:Hepatitis B / Q000378:metabolism* / Q000821:virology*; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D051272:Glucose Transporter Type 1; D006514:Hepatitis B Surface Antigens; D050505:Mutant Proteins; D010750:Phosphoproteins; D011498:Protein Precursors; D016271:Proto-Oncogene Proteins c-myc; D050986:YY1 Transcription Factor; C050807:presurface protein 2, hepatitis B surface antigen; D006003:Glycogen; D058570:TOR Serine-Threonine Kinases