Original Article
Copyright copy;2010 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Oct 21, 2010; 16(39): 4932-4937
Published online Oct 21, 2010. doi: 10.3748/wjg.v16.i39.4932
HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway
Hye-Lin Ha, Dae-Yeul Yu
Hye-Lin Ha, Dae-Yeul Yu, Disease Model Research Laboratory, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yuseong-gu, Daejeon 305-806, South Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 305-333, South Korea
Author contributions: Ha HL and Yu DY designed the research; Ha HL performed the research; Ha HL and Yu DY wrote the paper.
Supported by The 21st century Frontier Program in the Functional Human Genome Project, No. HGM0200934; the International Collaboration Program of Science and Technology, No. FGM0600914; the Research Program for New Drug Target Discovery Grant from the Ministry of Education, Science & Technology, No. NBM3300711; and the KRIBB Research Initiative Program Grant, No. KGM3320911
Correspondence to: Dae-Yeul Yu, PhD, Principal Researcher and Professor, Disease Model Research Laboratory, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yuseong-gu, Daejeon 305-806, South Korea. dyyu10@kribb.re.kr
Telephone: +82-42-8604422 Fax: +82-42-8604609
Received: April 22, 2010
Revised: June 4, 2010
Accepted: June 11, 2010
Published online: October 21, 2010
Abstract

AIM: To investigate the role of hepatitis B virus X-protein (HBx)-induced reactive oxygen species (ROS) on liver carcinogenesis in HBx transgenic mice and HepG2-HBx cells.

METHODS: Cell growth rate was analyzed, and through western blotting, mitogenic signaling was observed. Endogenous ROS from wild and HBx transgenic mice and HepG2-Mock and HBx cells were assayed by FACScalibur. Identification of oxidized and reduced phosphatase and tensin homolog (PTEN) was analyzed through N-ethylmaleimide alkylation, nonreducing electrophoresis.

RESULTS: We observed that the cell-proliferation-related phosphoinositide 3-kinase/Akt pathway is activated by HBx in vivo and in vitro. Increased ROS were detected by HBx. Tumor suppressor PTEN, via dephosphorylation of Akt, was oxidized and inactivated by increased ROS. Increased oxidized PTEN activated the mitogenic pathway through over-activated Akt. However, treatment with ROS scavenger N-acetyl cysteine can reverse PTEN to a reduced form. Endogenously produced ROS also stimulated HBx expression.

CONCLUSION: HBx induced ROS promoted Akt pathways via oxidized inactive PTEN. HBx and ROS maintained a positive regulatory loop, which aggravated carcinogenesis.

Keywords: Hepatitis B virus X protein; Hepatocellular carcinoma; Akt; Reactive oxygen species; Phosphatase and tensin homolog