Epstein-Barr virus-specific methylation of human genes in gastric cancer cells

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  • Ryan, Julie L
    • Other Affiliation: Departments of Dermatology & Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642-8704, USA
  • Jones, Richard J
    • Other Affiliation: Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX 77054, USA
  • Kenney, Shannon C
    • Other Affiliation: Departments of Oncology and Medicine, McArdle Laboratory, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA
  • Rivenbark, Ashley G
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Tang, Weihua
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Knight, Elizabeth RW
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Coleman, William
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Gulley, Margaret L
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
Abstract
  • Abstract Background Epstein-Barr Virus (EBV) is found in 10% of all gastric adenocarcinomas but its role in tumor development and maintenance remains unclear. The objective of this study was to examine EBV-mediated dysregulation of cellular factors implicated in gastric carcinogenesis. Methods Gene expression patterns were examined in EBV-negative and EBV-positive AGS gastric epithelial cells using a low density microarray, reverse transcription PCR, histochemical stains, and methylation-specific DNA sequencing. Expression of PTGS2 (COX2) was measured in AGS cells and in primary gastric adenocarcinoma tissues. Results In array studies, nearly half of the 96 human genes tested, representing 15 different cancer-related signal transduction pathways, were dysregulated after EBV infection. Reverse transcription PCR confirmed significant impact on factors having diverse functions such as cell cycle regulation (IGFBP3, CDKN2A, CCND1, HSP70, ID2, ID4), DNA repair (BRCA1, TFF1), cell adhesion (ICAM1), inflammation (COX2), and angiogenesis (HIF1A). Demethylation using 5-aza-2'-deoxycytidine reversed the EBV-mediated dysregulation for all 11 genes listed here. For some promoter sequences, CpG island methylation and demethylation occurred in an EBV-specific pattern as shown by bisulfite DNA sequencing. Immunohistochemistry was less sensitive than was western blot for detecting downregulation of COX2 upon EBV infection. Virus-related dysregulation of COX2 levels in vitro was not recapitulated in vivo among naturally infected gastric cancer tissues. Conclusions EBV alters human gene expression in ways that could contribute to the unique pathobiology of virus-associated cancer. Furthermore, the frequency and reversability of methylation-related transcriptional alterations suggest that demethylating agents have therapeutic potential for managing EBV-related carcinoma.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Julie L Ryan et al.; licensee BioMed Central Ltd.
Journal title
  • Infectious Agents and Cancer
Journal volume
  • 5
Journal issue
  • 1
Page start
  • 27
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1750-9378
Bibliographic citation
  • Infectious Agents and Cancer. 2010 Dec 31;5(1):27
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • March 18, 2016

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