title: Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma.
abstract: CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV-associated gastric carcinoma (GC). Aberrant promoter methylation and expression loss of PTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohistochemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. PTEN abnormalities were reiterated in GC cell lines MKN-1 and MKN-7 infected with recombinant EBV, and DNA methyltransferase 1 (DNMT1) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-1 similarly showed that viral latent membrane protein 2A (LMP2A) up-regulated DNMT1, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A-mediated DNMT1 overexpression. Immunohistochemistry for both pSTAT3 and DNMT1 showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMP2A induces the phosphorylation of STAT3, which activates DNMT1 transcription and causes PTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer.
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Hino
authors.forename: Hiroshi
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authors.lastname: Uozaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Murakami
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ushiku
authors.forename: Aya
authors.initials: A
authors.lastname: Shinozaki
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakaya
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakatani
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takada
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama