Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis.
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.
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan.
Han-Chieh
HC
Wu
Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
Hung-Wen
HW
Tsai
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan.
Chiao-Fang
CF
Teng
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan.
Wen-Chuan
WC
Hsieh
Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
Yih-Jyh
YJ
Lin
Institute of Molecular and Cellular Biology and Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan.
Lily Hui-Ching
LH
Wang
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen 361102, China.
Quan
Q
Yuan
National 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.
Ih-Jen
IJ
Su
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology*; D002472:Cell Transformation, Viral / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006509:Hepatitis B / Q000150:complications; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D006514:Hepatitis B Surface Antigens; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
Ground-glass hepatocytes; HBx; Hepatocellular carcinoma; Pre-S2 deletion mutant; mTOR signals