DNA Methylation of Interferon Regulatory Factors in Gastric Cancer and Noncancerous Gastric Mucosae

Overview

Journal Cancer Sci

Specialty Oncology

Date 2010 May 29

PMID 20507321

Citations 29

Authors

Masaki Yamashita

Minoru Toyota

Hiromu Suzuki

Masanori Nojima

Eiichiro Yamamoto

Seiko Kamimae

Yoshiyuki Watanabe

Masahiro Kai

Hirofumi Akashi

Reo Maruyama

Yasushi Sasaki

Hiroo Yamano

Tamotsu Sugai

Yasuhisa Shinomura

Kohzoh Imai

Takashi Tokino

Fumio Itoh

Affiliations

Soon will be listed here.

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.

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References

Muller H, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M . Methylation changes in faecal DNA: a marker for colorectal cancer screening?. Lancet. 2004; 363(9417):1283-5. DOI: 10.1016/S0140-6736(04)16002-9. View

Smits K, Cleven A, Weijenberg M, Hughes L, Herman J, de Bruine A . Pharmacoepigenomics in colorectal cancer: a step forward in predicting prognosis and treatment response. Pharmacogenomics. 2008; 9(12):1903-16. DOI: 10.2217/14622416.9.12.1903. View

Takaoka A, Tamura T, Taniguchi T . Interferon regulatory factor family of transcription factors and regulation of oncogenesis. Cancer Sci. 2008; 99(3):467-78. PMC: 11159419. DOI: 10.1111/j.1349-7006.2007.00720.x. View

Satoh A, Toyota M, Ikeda H, Morimoto Y, Akino K, Mita H . Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells. Oncogene. 2004; 23(55):8876-86. DOI: 10.1038/sj.onc.1208144. View

Ahlquist D . Next-generation stool DNA testing: expanding the scope. Gastroenterology. 2009; 136(7):2068-73. DOI: 10.1053/j.gastro.2009.04.025. View

Ortmann C, Burchert A, Holzle K, Nitsche A, Wittig B, Neubauer A . Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region. Nucleic Acids Res. 2006; 33(21):6895-905. PMC: 1310901. DOI: 10.1093/nar/gki1001. View

Kusano M, Toyota M, Suzuki H, Akino K, Aoki F, Fujita M . Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus. Cancer. 2006; 106(7):1467-79. DOI: 10.1002/cncr.21789. View

Reu F, Bae S, Cherkassky L, Leaman D, Lindner D, Beaulieu N . Overcoming resistance to interferon-induced apoptosis of renal carcinoma and melanoma cells by DNA demethylation. J Clin Oncol. 2006; 24(23):3771-9. DOI: 10.1200/JCO.2005.03.4074. View

Maruyama R, Aoki F, Toyota M, Sasaki Y, Akashi H, Mita H . Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Cancer Res. 2006; 66(9):4574-83. DOI: 10.1158/0008-5472.CAN-05-2562. View

10.

Akino K, Toyota M, Suzuki H, Imai T, Maruyama R, Kusano M . Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer Sci. 2006; 98(1):88-95. PMC: 11158324. DOI: 10.1111/j.1349-7006.2006.00351.x. View

11.

Suzuki H, Tokino T, Shinomura Y, Imai K, Toyota M . DNA methylation and cancer pathways in gastrointestinal tumors. Pharmacogenomics. 2008; 9(12):1917-28. DOI: 10.2217/14622416.9.12.1917. View

12.

Ishida S, Yamashita T, Nakaya U, Tokino T . Adenovirus-mediated transfer of p53-related genes induces apoptosis of human cancer cells. Jpn J Cancer Res. 2000; 91(2):174-80. PMC: 5926321. DOI: 10.1111/j.1349-7006.2000.tb00929.x. View

13.

Yanagihara K, Ito A, Toge T, Numoto M . Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 1993; 53(23):5815-21. View

14.

Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S . Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis. 2007; 28(12):2459-66. DOI: 10.1093/carcin/bgm178. View

15.

Barnes B, Kellum M, Pinder K, Frisancho J, Pitha P . Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 2003; 63(19):6424-31. View

16.

Hellebrekers D, Lentjes M, van den Bosch S, Melotte V, Wouters K, Daenen K . GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. Clin Cancer Res. 2009; 15(12):3990-7. DOI: 10.1158/1078-0432.CCR-09-0055. View

17.

Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, Sudo Y . Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell. 1988; 54(6):903-13. DOI: 10.1016/s0092-8674(88)91307-4. View

18.

Sugai T, Habano W, Jiao Y, Suzuki M, Takagi R, Otsuka K . Analysis of allelic imbalances at multiple cancer-related chromosomal loci and microsatellite instability within the same tumor using a single tumor gland from colorectal carcinomas. Int J Cancer. 2004; 114(3):337-45. DOI: 10.1002/ijc.20689. View

19.

Shou J, Soriano R, Hayward S, Cunha G, Williams P, Gao W . Expression profiling of a human cell line model of prostatic cancer reveals a direct involvement of interferon signaling in prostate tumor progression. Proc Natl Acad Sci U S A. 2002; 99(5):2830-5. PMC: 122433. DOI: 10.1073/pnas.052705299. View

20.

Watanabe Y, Toyota M, Kondo Y, Suzuki H, Imai T, Ohe-Toyota M . PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer. Clin Cancer Res. 2007; 13(16):4786-94. DOI: 10.1158/1078-0432.CCR-07-0305. View