title: DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae.
abstract: Interferon regulatory factors (IRFs) are transcription factors known to play key roles in innate and adaptive immune responses, cell growth, apoptosis, and development. Their function in tumorigenesis of gastric cancer remains to be determined, however. In the present study, therefore, we examined epigenetic inactivation of IRF1-9 in a panel of gastric cancer cell lines. We found that expression of IRF4, IRF5, and IRF8 was frequently suppressed in gastric cancer cell lines; that methylation of the three genes correlated with their silencing; and that treating the cells with the demethylating agent 5-aza-2'-deoxycytidine (DAC) restored their expression. Expression of IRF5 in cancer cells was enhanced by the combination of DAC treatment and adenoviral vector-mediated expression of p53, p63, or p73. Interferon-gamma-induced expression of IRF8 was also enhanced by DAC. Moreover, treating gastric cancer cells with DAC enhanced the suppressive effects of interferon-alpha, interferon-beta, and interferon-gamma on cell growth. Among a cohort of 455 gastric cancer and noncancerous gastric tissue samples, methylation of IRF4 was frequently observed in both gastric cancer specimens and noncancerous specimens of gastric mucosa from patients with multiple gastric cancers, which suggests IRF4 methylation could be a useful molecular marker for diagnosing recurrence of gastric cancers. Our findings indicate that epigenetic IRF inactivation plays a key role in tumorigenesis of gastric cancer, and that inhibition of DNA methylation may restore the antitumor activity of interferons through up-regulation of IRFs.
authors.affiliation: Department of Gastroenterology and Hepatology, St. Marianna Medical University, School of Medicine, Kawasaki, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Seiko
authors.initials: S
authors.lastname: Kamimae
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akashi
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yamano
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
mesh_terms: D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D000077209:Decitabine; D015536:Down-Regulation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D001374:Azacitidine; D004273:DNA, Neoplasm; D000077209:Decitabine; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C431713:IRF5 protein, human