Hepatitis B Virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis

Hui Ching Wang, Wen-Ya Huang, Ming-Derg Lai, Ih Jen Su

Research output: Contribution to journalReview article

164 Citations (Scopus)

Abstract

Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre-S1 (ΔS1-LHBs) and pre-S2 (ΔS2-LHBs) regions in ground glass hepatocytes. The pre-S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre-S mutants, particularly ΔS2-LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)-positive chronic HBV infection, ranging from 6% before the 3rd decade to 35% in the 6th decade. In HCC patients, the two pre-S mutants were detected in 60% of HCC patients, in the serum and in HCC tissues. Pre-S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre-S mutant LHBs can upregulate cyclooxygenase-2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre-S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre-S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre-S mutants in HBV-related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress.

Original languageEnglish
Pages (from-to)683-688
Number of pages6
JournalCancer Science
Volume97
Issue number8
DOIs
Publication statusPublished - 2006 Aug 1

Fingerprint

Endoplasmic Reticulum Stress
Hepatitis B virus
Hepatocellular Carcinoma
Hepatocytes
Cyclin A
Hepatitis B e Antigens
Genomic Instability
Insertional Mutagenesis
Chronic Hepatitis B
Virus Diseases
Cyclooxygenase 2
Hepatitis B Surface Antigens
Hepatitis B
Endoplasmic Reticulum
Transgenic Mice
DNA Damage
Glass
Cell Cycle
Carcinogenesis
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Hepatitis B Virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis",
abstract = "Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre-S1 (ΔS1-LHBs) and pre-S2 (ΔS2-LHBs) regions in ground glass hepatocytes. The pre-S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre-S mutants, particularly ΔS2-LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)-positive chronic HBV infection, ranging from 6{\%} before the 3rd decade to 35{\%} in the 6th decade. In HCC patients, the two pre-S mutants were detected in 60{\%} of HCC patients, in the serum and in HCC tissues. Pre-S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre-S mutant LHBs can upregulate cyclooxygenase-2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre-S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre-S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre-S mutants in HBV-related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress.",
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Hepatitis B Virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. / Wang, Hui Ching; Huang, Wen-Ya; Lai, Ming-Derg; Su, Ih Jen.

In: Cancer Science, Vol. 97, No. 8, 01.08.2006, p. 683-688.

Research output: Contribution to journalReview article

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