Hepatitis B Virus Pre-S2 Mutant Induces Aerobic Glycolysis through Mammalian Target of Rapamycin Signal Cascade

Chiao-Fang Teng; Wen-Chuan Hsieh; Han-Chieh Wu; Yih-Jyh Lin; Hung-Wen Tsai; Wenya Huang; Ih-Jen Su

doi:10.1371/journal.pone.0122373

Hepatitis B Virus Pre-S2 Mutant Induces Aerobic Glycolysis through Mammalian Target of Rapamycin Signal Cascade

PLoS One. 2015 Apr 24;10(4):e0122373. doi: 10.1371/journal.pone.0122373. eCollection 2015.

Authors

Chiao-Fang Teng¹, Wen-Chuan Hsieh¹, Han-Chieh Wu¹, Yih-Jyh Lin², Hung-Wen Tsai³, Wenya Huang⁴, Ih-Jen Su⁵

Affiliations

¹ National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
² Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
³ Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.
⁴ Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University College of Medicine, Tainan, Taiwan.
⁵ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinoma, Hepatocellular / etiology
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Cycle Proteins
Cell Line
Glucose Transporter Type 1 / metabolism
Glycogen / metabolism
Glycolysis
Hepatitis B / metabolism*
Hepatitis B / virology*
Hepatitis B Surface Antigens / genetics
Hepatitis B Surface Antigens / metabolism*
Hepatitis B virus / genetics
Hepatitis B virus / metabolism*
Humans
Immunohistochemistry
Liver Neoplasms / etiology
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Mice
Mice, Transgenic
Mutant Proteins*
Phosphoproteins / metabolism
Protein Precursors / genetics
Protein Precursors / metabolism*
Proto-Oncogene Proteins c-myc / metabolism
Signal Transduction*
TOR Serine-Threonine Kinases / metabolism*
YY1 Transcription Factor / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
EIF4EBP1 protein, human
Glucose Transporter Type 1
Hepatitis B Surface Antigens
Mutant Proteins
Phosphoproteins
Protein Precursors
Proto-Oncogene Proteins c-myc
YY1 Transcription Factor
presurface protein 2, hepatitis B surface antigen
Glycogen
TOR Serine-Threonine Kinases

Grants and funding

The authors received a grant from National Health Research Institutes (grant number: 03A1-IVPP20-014; http://www.nhri.org.tw/NHRI_WEB/nhriw001Action.do). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.