15 research outputs found

    Matrix Metalloproteinase-1 (MMP-1) Promoter Polymorphisms are Well Linked with Lower Stomach Tumor Formation in Eastern Indian Population

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    Expression of matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, plays a major role in cellular invasion during development of gastric cancer, a leading cause of death worldwide. A single-nucleotide polymorphism (SNP) 21607 1G/2G site of the MMP-1 gene promoter has been reported to alter transcription level. While the importance’s of other SNPs in the MMP-1 promoter have not yet been studied in gastric cancer, our aim was to investigate MMP-1 gene promoter polymorphisms and gastric cancer susceptibility in eastern Indian population. A total of 145 gastric cancer patients and 145 healthy controls were genotyped for MMP-1 21607 1G/2G (rs1799750) by PCR-restriction fragment length polymorphism (RFLP), while MMP-1 2519 A/G (rs1144393), MMP-1 2422 T/A (rs475007), MMP-1 2340 T/C (rs514921) and MMP-1 2320 T/C (rs494379) were genotyped by DNA sequencing. A positive association was found with MMP-1 2422 T/A SNP that showed significant risk for regional lymph node metastasis (P = 0.021, Odd’s ratio (OR) = 3.044, Confidence intervals (CI) = 1.187– 7.807). In addition, we found a significant association with lower stomach tumor formation among gastric cancer patients for three adjacent polymorphisms near the transcriptional start sites of [MMP-1 2422 T/A (P = 0.043, OR = 2.182, CI = 1.03– 4.643), MMP-1 2340 T/C (P = 0.075, OR = 1.97, CI = 0.94–4.158) and MMP-1 2320 T/C (P = 0.034, OR = 2.224, CI = 1.064– 40731)]. MMP-1 level in patients’ serum was correlated with MMP-1 promoter haplotypes conferring these three SNPs to evaluate the functional importance of these polymorphisms in lower stomach tumor formation and significant correlation was observed. Furthermore, MMP-1 2519 A/G polymorphism displayed poor cellular differentiation (P = 0.024, OR = 3.8, CI = 1.69–8.56) attributing a higher risk of cancer progression.In conclusion, MMP-1 proximal promoter SNPs are associated with the risk of lower stomach tumor formation and node metastasis in eastern Indian population

    Attenuation of Helicobacter pylori-induced gastric inflammation by prior cag− strain (AM1) infection in C57BL/6 mice

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    Helicobacter pylori, colonize in stomach of ~50% of the world population. cag pathogenicity Island of H. pylori is one of the important virulent factors that attributed to gastric inflammation. Coinfection with H. pylori strain with different genetic makeup alters the degree of pathogenicity and susceptibility towards antibiotics. The present study investigates host immunomodulatory effects of H. pylori infection by both cag+ strain (SS1) and cag− strain (AM1). C57BL/6 mice were infected with AM1 or SS1 strain as well as AM1 followed by SS1 (AM1/SS1) and vice versa. Results: Mice infected with AM1/SS1 strain exhibited less gastric inflammation and reduced proMMP9 and proMMP3 activities in gastric tissues as compared to SS1/SS1 and SS1/AM1 infected groups. The expression of both MMP9 and MMP3 followed similar trend like activity in infected tissues. Both Th1 and Th17 responses were induced by SS1 strain more profoundly than AM1 strain infection which induced solely Th1 response in spleen and gastric tissues. Moreover, IFN-γ, TNF-α, IL-1β and IL-12 were significantly downregulated in mice spleen and gastric tissues infected by AM1/SS1 compared to SS1/SS1 but not with SS1/AM1 coinfection. Surprisingly, IL-17 level was dampened significantly in AM1/ SS1 compared to SS1/AM1 coinfected groups. Furthermore, number of Foxp3+ T-regulatory (Treg) cells and immunosuppressive cytokines like IL-10 and TGF-β were reduced in AM1/SS1 compared to SS1/SS1 and SS1/AM1 coinfected mice gastric tissues. Conclusions: These data suggested that prior H. pylori cag− strain infection attenuated the severity of gastric pathology induced by subsequent cag+ strain in C57BL/6 mice. Prior AM1 infection induced Th1 cytokine IFN-γ, which reduced the Th17 response induced by subsequent SS1 infection. The reduced gastritis in AM1/SS1-infected mice might also be due to enrichment of AM1- primed Treg cells in the gastric compartment which inhibit Th1 and Th17 responses to subsequent SS1 infection. In summary, prior infection by non-virulent H. pylori strain (AM1) causes reduction of subsequent virulent strain (SS1) infection by regulation of inflammatory cytokines and MMPs expressio

    Role of matrix metalloproteinases and cytokines during Helicobacter pylori infection

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    The possible existence of bacteria in human stomach was believed for more than a century. These bacteria, however, were thought to be ingested from food rather than true gastric colonizers. By the late 19th and early 20th centuries, several investigators had reported the presence of spiral microorganisms in the stomach of animals and human (Kusters, van Vliet et al. 2006). In 1989, Walery Jaworski described spiral organisms in sediment washings of humans. He suggested that these organisms might be involved with gastric disease (Kidd and Modlin 1998). In 1892, Giulio Bizzozero observed spiral organisms in the stomach of dogs (Mazzarello, Calligaro et al. 2001). Soon afterward, similar spiral bacteria were observed in humans who had peptic ulcer disease or gastric cancer (Krienitz 1906). Although, throughout most of the 20th century, peptic ulcer disease was thought to be a chronic, incurable disease caused by gastric juice corroding vulnerable mucosa; and neutralization of gastric acid was the mean of disease management. About 20 years ago, Barry Marshall and Robin Warren described the successful isolation and culture of a spiral bacterial species, later known as Helicobacter pylori, from the human stomach (1983). The isolation of curved bacilli from patients with chronic gastritis sparked revolutions in the fields of gastroenterology, microbiology and molecular biology. Self-ingestion experiments by Marshall (Marshall, Armstrong et al. 1985) and Warren and later experiments with volunteers (Morris, Ali et al. 1991) demonstrated that these bacteria can colonize the human stomach, thereby inducing inflammation of the gastric mucosa. The etiological role of these bacteria in the development of peptic ulcer disease and gastric cancer was considered at that time, and patients were sometimes even treated with high doses of the antimicrobial compound bismuth (Kusters, van Vliet et al. 2006). Although the initial cultures from patients were negative, accidentally one culture was incubated for 5 days over an Easter holiday and the first colonies were observed in 1982 (Marshall and Warren 1984). They contested the prevailing notion by showing that peptic ulcer disease is an infectious disease caused by H. pylori. For this revolutionary work, Marshall and Warren were awarded the 2005 Nobel Prize for Physiology or Medicine. The organism was initially named “Campylobacter- like organism,

    Haplotype effect on serum MMP-1 concentration.

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    <p>Serum MMP-1 level in patients with lower stomach cancer with risk haplotypes (n = 54), and upper stomach cancer with non risk haplotypes (n = 15) were compared by ELISA. Results showed patients with lower stomach cancer exhibit a 1.43 fold higher MMP-1 level than in upper stomach cancer patients (p<0.05 by t-test) (box whisker diagram).</p

    Association between the genotypes of MMP-1 SNPs and clinicopathological characteristics of gastric cancer patients.

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    <p>P value, ORs and 95% CIs were calculated by unconditional binary logistic regression (using SPSS v16 software) with respective reference genotypes. (a) Adjusted with Sex. (b) Adjusted with Age. (c) Adjusted with Age, Sex, and Addiction. Values in bold indicate positive significance (P<0.05). (*) Histological classification is dependent on the basis of glandular architecture of adenocarcinoma. WD = Well differentiated, MD = Moderately differentiated, PD = poorly differentiated. (¥) Tumor stage is classified according to the criterion of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) TNM stage grouping <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088040#pone.0088040-Inoue1" target="_blank">[25]</a>. (#) Depth of tumor defined according to the criterion of AJCC.</p

    Association of increasing order of MMP-1 polymorphic variant alleles in haplotypes with Lower stomach gastric cancer risk.

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    <p>Haplotypes order as MMP-1.1-MMP-1.2-MMP-1.3-MMP-1.4-MMP-1.5.</p><p>(a) two sided χ<sup>2</sup> Association P value, OR = Odds ratio, CI = Confidence Interval, Ref = Reference haplotype to calculate OR. Other possible combinations of linked loci are omitted because of null frequency in the population. Haplotype frequency and haplotype association test performed using Haploview4.2 software. Haplotype numbers denote the number of risk allele(s) present in the haplotypes.</p
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