The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium

Tomiyasu Arisawa, Tomomitsu Tahara, Tomoyuki Shibata, Mitsuo Nagasaka, Masakatsu Nakamura, Yoshio Kamiya, Hiroshi Fujita, Daisuke Yoshioka, Yuko Arima, Masaaki Okubo, Ichiro Hirata, Hiroshi Nakano

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Abstract

Aberrant promoter methylation is an important mechanism for gene silencing. Inflammation-related reactive oxygens contribute to this CpG island methylation. The nuclear factor-erythroid 2-related factor 2 gene (Nrf2) is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene and the CpG island methylation in non-cancerous gastric mucosa. The study was performed in 85 subjects (46 without gastric malignancies, non-GC group, and 39 with gastric cancer, GC group). The promoter methylation status of p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by methylation-specific-polymerase chain reaction. The Nrf2 gene genotypes were determined by the PCR-SSCP method. In the 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16, none for p21. The frequency of the methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95% CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was much higher in GC group (p=0.0023). The Nrf2 -686/-684 G/ G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95% CI, 1.26-8.59; p=0.015, and OR, 0.38; 95% CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95% CI, 1.14-7.36; p=0.026, and OR, 0.33; 95% CI, 0.13-0.88; p=0.027, respectively). Our results suggested that the promoter polymorphisms of Nrf2 gene may affect the methylation status of tumor-related genes, especially the p14 gene, under the influence of H. pylori-induced gastric inflammation.

Original languageEnglish
Pages (from-to)211-216
Number of pages6
JournalOncology reports
Volume19
Issue number1
Publication statusPublished - 01-01-2008

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Arisawa, T., Tahara, T., Shibata, T., Nagasaka, M., Nakamura, M., Kamiya, Y., Fujita, H., Yoshioka, D., Arima, Y., Okubo, M., Hirata, I., & Nakano, H. (2008). The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium. Oncology reports, 19(1), 211-216.