Increased risk of intestinal type of gastric adenocarcinoma in Japanese women associated with long forms of CCTTT pentanucleotide repeat in the inducible nitric oxide synthase promoter

International Agency for Research on Cancer, 150 Cours Albert Thomas, F 69372 Lyon Cedex 08, France.
Cancer Letters (Impact Factor: 5.62). 02/2005; 217(2):197-202. DOI: 10.1016/j.canlet.2004.09.002
Source: PubMed


Tandem repeat number polymorphism of a CCTTT pentanucleotide in the promoter region of the inducible nitric oxide synthase gene (iNOS) and a polymorphism of the interleukin-1beta (IL-1B) promoter at position -31 were analyzed in DNA samples from 181 Japanese control subjects and 158 gastric cancer patients, including 96 intestinal type and 62 diffuse type. An association between the intestinal type of gastric adenocarcinoma and higher promoter activity of the iNOS gene was found in women, especially those having higher promoter activity of the IL-1B gene and without a history of smoking. Our results imply that chronic inflammation caused by excess nitric oxide generated by iNOS contributes to Helicobacter pylori-induced gastric cancer.

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    • "The genes coding for all these enzymes are polymorphic [1–3, 12, 16, 19–21]. The most common single-nucleotide polymorphism (SNP) of the MnSOD gene results in alanine (Ala) to valine (Val) substitution (Ala-9Val); of the ECSOD gene results in arginine (Arg) to glycine (Gly) change (Arg213Gly); and of the CAT gene results in cytosine (C) to thymine (T) substitution (−262C > T) [12, 13, 22]. "
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    ABSTRACT: This study investigated the influence of gene-gene and gene-environment interactions on the risk of developing asbestosis. The study comprised 262 cases with asbestosis and 265 controls with no asbestos-related disease previously studied for MnSOD, ECSOD, CAT, GSTT1, GSTM1, GSTP1, and iNOS polymorphisms. Data on cumulative asbestos and smoking were available for all subjects. To assess gene-gene and gene-environmental interactions, logistic regression was used. The associations between MnSOD Ala -9Val polymorphism and the risk of asbestosis and between iNOS genotypes and asbestosis were modified by CAT -262 C > T polymorphism (P = 0.038; P = 0.031). A strong interaction was found between GSTM1-null polymorphism and smoking (P = 0.007), iNOS (CCTTT) n polymorphism and smoking (P = 0.054), and between iNOS (CCTTT) n polymorphism and cumulative asbestos exposure (P = 0.037). The findings of this study suggest that the interactions between different genotypes, genotypes and smoking, and between genotypes and asbestos exposure have an important influence on the development of asbestosis and should be seriously considered in future research on occupational/environmental asbestos-related diseases.
    07/2013; 2013(12):405743. DOI:10.1155/2013/405743
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    • "The CCTTT pentanucleotide repeats within the promotor region of the human iNOS gene have been associated with the biochemical promoter activity [19]. Several studies have suggested an association between inflammatory diseases or cancer and the number of the CCTTT repeats [18–21]. However, to our knowledge and according to the literature available, this polymorphism has not been studied so far in association with asbestosis. "
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    ABSTRACT: Asbestos, a known occupational pollutant, may upregulate the activity of inducible nitric oxide synthase (iNOS) and thus the production of nitric oxide (NO). This study investigated whether iNOS (CCTTT)n polymorphism is associated with an increased asbestosis risk in exposed workers. The study cohort consisted of 262 cases with asbestosis and 265 controls with no asbestos-related disease. For each subject the cumulative asbestos exposure data were available. The number of CCTTT repeats was determined following PCR amplification of the iNOS promoter region. Logistic regression was performed to estimate asbestosis risk. The OR of asbestosis was 1.20 (95% CI = 0.85–1.69) for the LL genotype compared to the combined SL and SS genotypes and 1.26 (95% CI = 0.86–1.85) for the LL genotype compared to the SL genotype. The results of this study are borderline significant and suggest a possible role of iNOS (CCTTT)n polymorphism in the risk of asbestosis; however, further studies are needed.
    BioMed Research International 05/2011; 2011:685870. DOI:10.1155/2011/685870 · 2.71 Impact Factor
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    • "Indeed, iNOS-deficient mice have a reduced incidence of gastric adenocarcinoma after H. pylori infection and challenge with a chemical carcinogen compared to normal mice [6]. Also, polymorphisms in the promoter region of iNOS, leading to a higher transcriptional activity, correlate with a higher incidence of the intestinal type of gastric cancer in Japanese women [21]. "
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    ABSTRACT: Infection with Helicobacter pylori triggers a chronic gastric inflammation that can progress to atrophy and gastric adenocarcinoma. Polarization of macrophages is a characteristic of both cancer and infection, and may promote progression or resolution of disease. However, the role of macrophages and their polarization during H. pylori infection has not been well defined. By using a mouse model of infection and gastric biopsies from 29 individuals, we have analyzed macrophage recruitment and polarization during H. pylori infection by flow cytometry and real-time PCR. We found a sequential recruitment of neutrophils, eosinophils and macrophages to the gastric mucosa of infected mice. Gene expression analysis of stomach tissue and sorted macrophages revealed that gastric macrophages were polarized to M1 after H. pylori infection, and this process was substantially accelerated by prior vaccination. Human H. pylori infection was characterized by a mixed M1/M2 polarization of macrophages. However, in H. pylori-associated atrophic gastritis, the expression of inducible nitric oxide synthase was markedly increased compared to uncomplicated gastritis, indicative of an enhanced M1 macrophage polarization in this pre-malignant lesion. These results show that vaccination of mice against H. pylori amplifies M1 polarization of gastric macrophages, and that a similar enhanced M1 polarization is present in human H. pylori-induced atrophic gastritis.
    PLoS ONE 11/2010; 5(11):e15018. DOI:10.1371/journal.pone.0015018 · 3.23 Impact Factor
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