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

Research output: Contribution to journalArticle

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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

Fingerprint

DNA Methylation
Methylation
Stomach
Epithelium
Genes
CpG Islands
Helicobacter pylori
Haplotypes
Alleles
Tumor Suppressor Protein p14ARF
p16 Genes
Inflammation
Single-Stranded Conformational Polymorphism
Polymerase Chain Reaction
Gene Silencing
Gastric Mucosa
Gene Frequency
Stomach Neoplasms
Neoplasms
Antioxidants

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Arisawa, Tomiyasu ; Tahara, Tomomitsu ; Shibata, Tomoyuki ; Nagasaka, Mitsuo ; Nakamura, Masakatsu ; Kamiya, Yoshio ; Fujita, Hiroshi ; Yoshioka, Daisuke ; Arima, Yuko ; Okubo, Masaaki ; Hirata, Ichiro ; Nakano, Hiroshi. / The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium. In: Oncology reports. 2008 ; Vol. 19, No. 1. pp. 211-216.
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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.",
author = "Tomiyasu Arisawa and Tomomitsu Tahara and Tomoyuki Shibata and Mitsuo Nagasaka and Masakatsu Nakamura and Yoshio Kamiya and Hiroshi Fujita and Daisuke Yoshioka and Yuko Arima and Masaaki Okubo and Ichiro Hirata and Hiroshi Nakano",
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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, vol. 19, no. 1, pp. 211-216.

The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium. / Arisawa, Tomiyasu; Tahara, Tomomitsu; Shibata, Tomoyuki; Nagasaka, Mitsuo; Nakamura, Masakatsu; Kamiya, Yoshio; Fujita, Hiroshi; Yoshioka, Daisuke; Arima, Yuko; Okubo, Masaaki; Hirata, Ichiro; Nakano, Hiroshi.

In: Oncology reports, Vol. 19, No. 1, 01.01.2008, p. 211-216.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium

AU - Arisawa, Tomiyasu

AU - Tahara, Tomomitsu

AU - Shibata, Tomoyuki

AU - Nagasaka, Mitsuo

AU - Nakamura, Masakatsu

AU - Kamiya, Yoshio

AU - Fujita, Hiroshi

AU - Yoshioka, Daisuke

AU - Arima, Yuko

AU - Okubo, Masaaki

AU - Hirata, Ichiro

AU - Nakano, Hiroshi

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

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