title: Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent.
abstract: Suppression of aberrant DNA methylation is a novel approach to cancer prevention, but, so far, the efficacy of the strategy has not been evaluated in cancers associated with chronic inflammation. Gastric cancers induced by Helicobacter pylori infection are known to involve aberrant DNA methylation and associated with severe chronic inflammation in their early stages. Here, we aimed to clarify whether suppression of aberrant DNA methylation can prevent H. pylori-induced gastric cancers using a Mongolian gerbil model. Administration of a DNA demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), to gerbils (0.125 mg/kg for 50-55 weeks) decreased the incidence of gastric cancers induced by H. pylori infection and N-methyl-N-nitrosourea (MNU) treatment from 55.2% to 23.3% (P < 0.05). In gastric epithelial cells, DNA methylation levels of six CpG islands (HE6, HG2, SB1, SB5, SF12, and SH6) decreased to 46% to 68% (P < 0.05) of gerbils without 5-aza-dC treatment. Also, the global DNA methylation level decreased from 83.0% ± 4.5% to 80.3% ± 4.4% (mean ± SD) by 5-aza-dC treatment (P < 0.05). By 5-aza-dC treatment, Il1b and Nos2 were downregulated (42% and 58% of gerbils without, respectively) but Tnf was upregulated (187%), suggesting that 5-aza-dC treatment induced dysregulation of inflammatory responses. No obvious adverse effect of 5-aza-dC treatment was observed, besides testicular atrophy. These results showed that 5-aza-dC treatment can prevent H. pylori-induced gastric cancers and suggested that removal of induced DNA methylation and/or suppression of DNA methylation induction can become a target for prevention of chronic inflammation-associated cancers.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Niwa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Toyoda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Mori
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000382:microbiology* / Q000517:prevention & control*; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002273:Carcinogens; D019175:DNA Methylation / Q000187:drug effects; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori / Q000502:physiology*; D008297:Male; D008770:Methylnitrosourea; D013274:Stomach Neoplasms / Q000235:genetics / Q000382:microbiology* / Q000517:prevention & control*
chemical_list: D002273:Carcinogens; D008770:Methylnitrosourea; D000077209:Decitabine; D015257:DNA-Cytosine Methylases; D001374:Azacitidine