Abstract
Epstein-Barr virus (EBV) is an important DNA virus which establishes latent infection in human malignancies. Expression of EBV-encoded genes in the associated tumors is strongly modulated by promoter CpG methylation of EBV genome. This study aimed to explore the methylation status of the promoters of EBV BamHI-A rightward frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) and their influence on transcriptional expression, to further understand the roles of BARF1 and BHRF1 in the occurrence of EBV-associated cancer. We evaluated the methylation status of BARF1 and BHRF1 promoters in 43 EBV-associated gastric carcinoma (EBVaGC) tissues and EBV-positive cell lines. Their expressions were evaluated by real-time quantitative PCR. We found that the promoters of BARF1 and BHRF1 were methylated by varying degrees in different EBV-positive cell lines and were almost hypermethylated in all EBVaGC tissues. The methylation status of BARF1 and BHRF1 promoters were significantly reduced by 5-Aza-CdR along with the increasing gene expressions. Hypermethylation of Ap and Hp mediates the frequent silencing of BARF1 and BHRF1 in EBV-associated tumors, which could be reactivated by a demethylation agent, suggesting that promoter demethylation and activation is important for BARF1 and BHRF1 transcription and their further action.
Highlights
Epstein-Barr virus (EBV) is a gamma DNA herpes virus that infects over 95% of the global population and remains an asymptomatic life-long infection [1]
Results showed that most CpG loci in the selected region of BamHI-A rightward frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) promoters were methylated in GT39, GT38, and Raji
BARF1 is a potent oncogene in EBV carcinomas and has a variety of important biological functions in the pathogenic and carcinogenic mechanism of EBV
Summary
Epstein-Barr virus (EBV) is a gamma DNA herpes virus that infects over 95% of the global population and remains an asymptomatic life-long infection [1]. B lymphocytes and epithelial cells are the major targets of EBV infection. As a common human tumor virus, EBV was shown to be associated with a vast number of human diseases, such as lymphomas, nasopharyngeal carcinoma (NPC), and gastric carcinoma [2]. Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype that accounts for approximately 10% of all gastric carcinomas worldwide. EBV was suggested to be a causal role in gastric carcinogenesis, intimately linked to pathogenesis and tumor maintenance [3,4,5]. Numerous studies revealed that genomic features of host DNA, mRNA, microRNA, and CpG methylation profiles were contributed to the carcinogenesis of EBVaGCs [6, 7]
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