Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes

Hui Ching Wang, Wen Tsan Chang, Wen Wei Chang, Han Chieh Wu, Wenya Huang, Huan Yao Lei, Ming Derg Lai, Nelson Fausto, Ih Jen Su

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)761-770
Number of pages10
JournalHepatology
Volume41
Issue number4
DOIs
Publication statusPublished - 2005 Apr

All Science Journal Classification (ASJC) codes

  • Hepatology

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