Cytosine methylation in EBV-mediated nasopharyngeal carcinoma in relation to nitrative stress

Nasopharyngeal carcinoma (NPC) is a malignancy with ethnic and geographic distribution in southern China. The pathogenesis of NPC is a complicated process involving environment factors, genetic susceptibility, infection with the Epstein-Barr virus (EBV) and epigenetic changes. Unlike all other head neck squamous cell carcinomas, NPC is strongly associated with EBV infection, which can mediate nitrative and oxidative DNA damage and epigenetic changes. Reactive nitrogen and oxygen species are considered to participate in inflammation-related carcinogenesis through DNA damage. It is reported that nitric oxide (NO) can activate DNA methyltransferase (DNMT) and modify CpG island methylation. We have found promoter hypermethylation in several candidate genes for tumor suppressor genes in NPC. By examined the expression levels of EBV encoded small RNA (EBER) s, the formation of 8-nitroguanine and 8-hydroxy-2′-deoxyguanosine (8-OHdG), DMNT1 and 5-methyl-dC in NPC biopsies and non-cancerous controls, we studied the relationship between EBV infection, inflammation and epigenetic modification in NPC. Strong DNA lesions were observed in cancer cells and inflammatory cells in stroma of NPC tumor biopsies. Intensive immunoreactivity of iNOS was detected in the cytoplasm of 8-nitroguanine-positive cancer cells. Significantly higher levels of serum 8-OHdG, IL-6 and higher titers of EB-viral capsid antigen-IgA were observed in NPC patients than those of controls. Interestingly, the results of EBER in situ hybridization showed significant association with DNMT1 and 5-methyl-dC. These results indicate that EBV-mediated inflammation may play a role in cytosine methylation during NPC development. [Copyright &y& Elsevier]