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Hum Pathol. 2014 Jun;45(6):1294-301. doi: 10.1016/j.humpath.2013.10.039. Epub 2014 Feb 28.

Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis.

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  • 1National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan.
  • 2Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
  • 3Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
  • 4Institute of Molecular and Cellular Biology and Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan.
  • 5National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen 361102, China.
  • 6National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan; Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan. Electronic address: suihjen@nhri.org.tw.

Abstract

Hepatitis B virus (HBV) X protein (HBx) and pre-S2 deletion mutant large surface antigens are oncoproteins that induce hepatocellular carcinoma (HCC). The interaction of these two oncoproteins in hepatocytes and its significance in tumorigenesis remain to be elucidated. In this study, we observed the co-expression of HBx with surface antigens in ground-glass hepatocytes in 5 of 20 hepatitis B surface antigen-positive livers. In vitro, hepatocytes co-expressing HBx and a pre-S2 mutant showed enhanced expression of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin signals. Transgenic mice harboring both HBx and pre-S2 mutant construct plasmids developed HCCs at an average of 15.1 months, earlier than animals carrying either HBx (16.9 months) or pre-S2 mutant (24.5 months) alone. The oncogenic signals of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin were sequentially and differentially activated at different stages in tumorigenesis. Phosphorylated mTOR was consistently activated in transgenic and human HCCs. We conclude that ground-glass hepatocytes co-expressing HBx and surface antigens exhibit enhanced oncogenic effects and tumorigenesis in chronic HBV infections. The mTOR signal cascade may be the key regulator in HBV tumorigenesis and may be useful targets in the design of HCC therapy.

Copyright © 2014. Published by Elsevier Inc.

KEYWORDS:

Ground-glass hepatocytes; HBx; Hepatocellular carcinoma; Pre-S2 deletion mutant; mTOR signals

PMID:
24767856
[PubMed - indexed for MEDLINE]
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