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.

Details

Title
Epstein-Barr virus-specific methylation of human genes in gastric cancer cells
Author
Ryan, Julie L; Jones, Richard J; Kenney, Shannon C; Rivenbark, Ashley G; Tang, Weihua; Knight, Elizabeth RW; Coleman, William B; Gulley, Margaret L
First page
27
Publication year
2010
Publication date
2010
Publisher
BioMed Central
e-ISSN
17509378
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
902317844
Copyright
© 2010 Ryan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.