Genetics, chemical carcinogens and latent Epstein-Barr virus (EBV) infection have been incriminated in the carcinogenesis of nasopharyngeal carcinoma (NPC) [Young and Rickinson(2004), Nature Rev Cancer 4:757-768]. However, what are the mechanisms of these factors contributing to NPC carcinogenesis have not been fully elucidated yet. Nitroso compounds in Cantonese salted fish and tumor promoting agents in Chinese herbal medicine and EBV latent membrane protein 1 (LMP1) have been suspected to participate in the tumorigenesis of NPC.

　　Genome instability (GI) is a hall mark of cancers and considered as either the cause or result of carcinogenesis. GI is increasingly prominent in the progression of NPC carcinogenesis. To elucidate the contribution of chemical carcinogens N-methyl-N’-nitro-N- nitrosoguanidine (MNNG), 12-O-tetradecanoyl phorbol-1, 3-acetate (TPA) and sodium butyrate and EBV infection in the carcinogenesis of NPC, EBV-negative cell lines (TW01 and HONE1) and their EBV-positive counter part cell lines (NA and HA) were treated with various combinations of these agents. Micronucleus formation was examined as the marker of GI. The results indicated the genome instability increased with the treatments in EBV-negative NPC cells but much more prominent in EBV-positive NPC cells concomitantly with the increases of EBV reactivation. Using siZta to inhibit the reactivation of EBV, the micronucleus formation was decreased in a dose-dependent manner suggesting EBV reactivation contributes most significantly in the induction of GI. Interestingly, a synergistic effect was observed when MMNG and TPA/ sodium butyrate were added together in the treatment of EBV-positive NPC cells.

　　Our results leads to a new hypothesis that, although chemical carcinogens and latent EBV infection contribute independently, the cooperation between chemical carcinogens and EBV contributes more importantly in the carcinogenesis of NPC through the reactivation of EBV.
Therefore, prevention of EBV reactivation appears to be more important in the control of NPC. Although vaccination against EBV may be useful, however, consider the cost-effectiveness, it may not be a good way in the prevention of NPC.