Chronic nonsteroidal anti-inflammatory drug (NSAID) use suppresses multiple CpG islands hyper methylation (CIHM) of tumor suppressor genes in the human gastric mucosa

Tomomitsu Tahara, Tomoyuki Shibata, Hiromi Yamashita, Masakatsu Nakamura, Daisuke Yoshioka, Masaaki Okubo, Ichiro Hirata, Tomiyasu Arisawa

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Abstract

There have been reports showing a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a major event in carcinogenesis. We investigated the CIHM status of non-cancerous gastric mucosa in chronic NSAID users and non-users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non-users. CIHM of p14(ARF), p16(INK4a), death-associated protein kinase (DAP-kinase), and E-cadherin (CDH1) genes were determined by methylation-specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non-users (p14: non-users vs users = 32.2% vs 9.8%, P = 0.003; p16: non-users vs users.= 35.0% vs 15.7%, P = 0.02; CDH1: non-users vs users = 36.1% vs 9.8%, P = 0.0009; CIHM high: non-users vs users = 44.4% vs 17.6%, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = -0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio [OR] = 0.17, 95% confidence interval [CI] = 0.06-0.48; p16: OR = 0.32, 95%.CI = 0.14-0.75; DAP-kinase: OR = 0.45, 95% CI =.0.22-0.92; CDH1: OR = 0.18, 95%.CI = 0.06-0.48; CIHM high: OR = 0.21, 95% CI = 0.09-0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation-related gastric carcinogenesis.

Original languageEnglish
Pages (from-to)1192-1197
Number of pages6
JournalCancer Science
Volume100
Issue number7
DOIs
Publication statusPublished - 24-06-2009

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CpG Islands
Gastric Mucosa
Tumor Suppressor Genes
Methylation
Anti-Inflammatory Agents
Pharmaceutical Preparations
Odds Ratio
Confidence Intervals
Death-Associated Protein Kinases
Drug Users
Carcinogenesis
Tumor Suppressor Protein p14ARF
Gastrointestinal Neoplasms
Helicobacter Infections
Cadherins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Tahara, Tomomitsu ; Shibata, Tomoyuki ; Yamashita, Hiromi ; Nakamura, Masakatsu ; Yoshioka, Daisuke ; Okubo, Masaaki ; Hirata, Ichiro ; Arisawa, Tomiyasu. / Chronic nonsteroidal anti-inflammatory drug (NSAID) use suppresses multiple CpG islands hyper methylation (CIHM) of tumor suppressor genes in the human gastric mucosa. In: Cancer Science. 2009 ; Vol. 100, No. 7. pp. 1192-1197.
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title = "Chronic nonsteroidal anti-inflammatory drug (NSAID) use suppresses multiple CpG islands hyper methylation (CIHM) of tumor suppressor genes in the human gastric mucosa",
abstract = "There have been reports showing a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a major event in carcinogenesis. We investigated the CIHM status of non-cancerous gastric mucosa in chronic NSAID users and non-users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non-users. CIHM of p14(ARF), p16(INK4a), death-associated protein kinase (DAP-kinase), and E-cadherin (CDH1) genes were determined by methylation-specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non-users (p14: non-users vs users = 32.2{\%} vs 9.8{\%}, P = 0.003; p16: non-users vs users.= 35.0{\%} vs 15.7{\%}, P = 0.02; CDH1: non-users vs users = 36.1{\%} vs 9.8{\%}, P = 0.0009; CIHM high: non-users vs users = 44.4{\%} vs 17.6{\%}, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = -0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio [OR] = 0.17, 95{\%} confidence interval [CI] = 0.06-0.48; p16: OR = 0.32, 95{\%}.CI = 0.14-0.75; DAP-kinase: OR = 0.45, 95{\%} CI =.0.22-0.92; CDH1: OR = 0.18, 95{\%}.CI = 0.06-0.48; CIHM high: OR = 0.21, 95{\%} CI = 0.09-0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation-related gastric carcinogenesis.",
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Chronic nonsteroidal anti-inflammatory drug (NSAID) use suppresses multiple CpG islands hyper methylation (CIHM) of tumor suppressor genes in the human gastric mucosa. / Tahara, Tomomitsu; Shibata, Tomoyuki; Yamashita, Hiromi; Nakamura, Masakatsu; Yoshioka, Daisuke; Okubo, Masaaki; Hirata, Ichiro; Arisawa, Tomiyasu.

In: Cancer Science, Vol. 100, No. 7, 24.06.2009, p. 1192-1197.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chronic nonsteroidal anti-inflammatory drug (NSAID) use suppresses multiple CpG islands hyper methylation (CIHM) of tumor suppressor genes in the human gastric mucosa

AU - Tahara, Tomomitsu

AU - Shibata, Tomoyuki

AU - Yamashita, Hiromi

AU - Nakamura, Masakatsu

AU - Yoshioka, Daisuke

AU - Okubo, Masaaki

AU - Hirata, Ichiro

AU - Arisawa, Tomiyasu

PY - 2009/6/24

Y1 - 2009/6/24

N2 - There have been reports showing a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a major event in carcinogenesis. We investigated the CIHM status of non-cancerous gastric mucosa in chronic NSAID users and non-users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non-users. CIHM of p14(ARF), p16(INK4a), death-associated protein kinase (DAP-kinase), and E-cadherin (CDH1) genes were determined by methylation-specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non-users (p14: non-users vs users = 32.2% vs 9.8%, P = 0.003; p16: non-users vs users.= 35.0% vs 15.7%, P = 0.02; CDH1: non-users vs users = 36.1% vs 9.8%, P = 0.0009; CIHM high: non-users vs users = 44.4% vs 17.6%, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = -0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio [OR] = 0.17, 95% confidence interval [CI] = 0.06-0.48; p16: OR = 0.32, 95%.CI = 0.14-0.75; DAP-kinase: OR = 0.45, 95% CI =.0.22-0.92; CDH1: OR = 0.18, 95%.CI = 0.06-0.48; CIHM high: OR = 0.21, 95% CI = 0.09-0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation-related gastric carcinogenesis.

AB - There have been reports showing a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a major event in carcinogenesis. We investigated the CIHM status of non-cancerous gastric mucosa in chronic NSAID users and non-users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non-users. CIHM of p14(ARF), p16(INK4a), death-associated protein kinase (DAP-kinase), and E-cadherin (CDH1) genes were determined by methylation-specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non-users (p14: non-users vs users = 32.2% vs 9.8%, P = 0.003; p16: non-users vs users.= 35.0% vs 15.7%, P = 0.02; CDH1: non-users vs users = 36.1% vs 9.8%, P = 0.0009; CIHM high: non-users vs users = 44.4% vs 17.6%, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = -0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio [OR] = 0.17, 95% confidence interval [CI] = 0.06-0.48; p16: OR = 0.32, 95%.CI = 0.14-0.75; DAP-kinase: OR = 0.45, 95% CI =.0.22-0.92; CDH1: OR = 0.18, 95%.CI = 0.06-0.48; CIHM high: OR = 0.21, 95% CI = 0.09-0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation-related gastric carcinogenesis.

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