Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes
Open Access
- 22 February 2005
- journal article
- viral hepatitis
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 41 (4), 761-770
- https://doi.org/10.1002/hep.20615
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. (HEPATOLOGY 2005.)This publication has 29 references indexed in Scilit:
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