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Hepatitis B virus pre‐S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes
Author(s) -
Wang HuiChing,
Chang WenTsan,
Chang WenWei,
Wu HanChieh,
Huang Wenya,
Lei HuanYao,
Lai MingDerg,
Fausto Nelson,
Su IhJen
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20615
Subject(s) - cyclin d1 , biology , carcinogenesis , cancer research , hepatitis b virus , hepatocyte , cirrhosis , endoplasmic reticulum , unfolded protein response , cell growth , downregulation and upregulation , cyclin a2 , cyclin a , cyclin e , cyclin , microbiology and biotechnology , cell cycle , virology , cell , medicine , virus , cancer , gene , in vitro , biochemistry , genetics
Abstract Naturally occurring mutants with a deletion in the pre‐S2 region of the large surface protein (ΔS2‐LHBs) are prevalent in serum and livers of patients with chronic hepatitis B virus (HBV) infection associated with cirrhosis. The ΔS2‐LHBs protein is retained in the endoplasmic reticulum (ER) and may induce ER stress. One interesting observation is the consistently clustered distribution of hepatocytes expressing ΔS2‐LHBs. In this study, complementary DNA microarray analysis identified cyclin A and several groups of genes as being significantly upregulated by ΔS2‐LHBs in the HuH‐7 cell line. This observation was confirmed in liver tissues. The induction of cyclin A expression may occur via the specific transactivator function of ΔS2‐LHBs independent of ER stress. In the presence of ΔS2‐LHBs, hepatocytes sustained cyclin A expression and cell cycle progression under ER stress and displayed increased BrdU incorporation with multinuclear formation. Furthermore, ΔS2‐LHBs could enhance anchorage‐independent cell growth in a nontransformed human hepatocyte line and induced nodular proliferation of hepatocytes in transgenic mice. In conclusion , these in vitro and in vivo data support a role for ΔS2‐LHBs in the hepatocyte hyperplasia and a likely role in the process of HBV‐related tumorigenesis. (H EPATOLOGY 2005.)