| Title | Hypermethylation of the interferon regulatory factor 5 promoter in Epstein-Barr virus-associated gastric carcinoma |
|---|---|
| Author | Seung Myung Dong1, Hyun Gyu Lee2, Sung-Gyu Cho2, Seung-Hyun Kwon2, Heejei Yoon2, Hyun-Jin Kwon2, Ji Hae Lee1, Hyemi Kim2,3, Pil-Gu Park2, Hoguen Kim3,4, S. Diane Hayward5, Jeon Han Park2, and Jae Myun Lee2,3* |
| Address | 1Research Institute, National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea, 2Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea, 3Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea, 4Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea, 5Department of Oncology Johns Hopkins University School of Medicine, Baltimore, MD, USA |
| Bibliography | Journal of Microbiology, 53(1),70-76, 2015, |
| DOI | 10.1007/s12275-014-4654-3 |
| Key Words | interferon regulatory factor 5, Epstein-Barr virus, gastric carcinoma, CpG island, promoter methylation |
| Abstract | Interferon regulatory factor-5 (IRF-5), a member of the mammalian IRF transcription factor family, is regulated by p53, type I interferon and virus infection. IRF-5 participates in virus-induced TLR-mediated innate immune responses and may play a role as a tumor suppressor. It was suppressed in various EBV-infected transformed cells, thus it is valuable to identify the suppression mechanism. We focused on a promoter CpG islands methylation, a kind of epigenetic regulation in EBV-associated Burkitt’s lymphomas (BLs) and gastric carcinomas. IRF-5 is not detected in most of EBV-infected BL cell lines due to hypermethylation of IRF-5 distal promoter (promoter-A), which was restored by a demethylating agent, 5-aza-2-deoxycytidine. Hypomethylation of CpG islands in promoter-A was observed only in EBV type III latent infected BL cell lines (LCL and Mutu III). Similarly, during EBV infection to Akata-4E3 cells, IRF-5 was observed at early time periods (2 days to 8 weeks), concomitant unmethylation of promoter-A, but suppressed in later infection periods as observed in latency I BL cell lines. Moreover, hypermethylation in IRF-5 promoter-A region was also observed in EBV-associated gastric carcinoma (EBVaGC) cell lines or primary gastric carcinoma tissues, which show type I latent infection. In summary, IRF-5 is suppressed by hypermethylation of its promoter-A in most of EBV-infected transformed cells, especially BLs and EBVaGC. EBV-induced carcinogenesis takes an advantage of proliferative effects of TLR signaling, while limiting IRF-5 mediated negative effects in the establishment of EBVaGCs. |