DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae.
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.
Yamashita
Masaki
M
Department of Gastroenterology and Hepatology, St. Marianna Medical University, School of Medicine, Kawasaki, Japan.
Toyota
Minoru
M
Suzuki
Hiromu
H
Nojima
Masanori
M
Yamamoto
Eiichiro
E
Kamimae
Seiko
S
Watanabe
Yoshiyuki
Y
Kai
Masahiro
M
Akashi
Hirofumi
H
Maruyama
Reo
R
Sasaki
Yasushi
Y
Yamano
Hiroo
H
Sugai
Tamotsu
T
Shinomura
Yasuhisa
Y
Imai
Kohzoh
K
Tokino
Takashi
T
Itoh
Fumio
F
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
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