New Aspects of Helicobacter pylori Infection Involvement in Gastric Oncogenesis

Kountouras, Jannis; Zavos, Christos; Chatzopoulos, Dimitrios; Katsinelos, Panagiotis

doi:10.1016/j.jss.2007.06.011

Cited by 68 publications

(53 citation statements)

References 41 publications

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“…The multistep model of gastric carcinoma development postulates that carcinogenesis is initiated by inflammation caused by H. pylori infection as well as by dietary exposure to salt and nitrate, which cause DNA damage (38). To investigate this further, we have identified three mechanisms by which H. pylori may provoke a loss of genomic integrity and promote transformation.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Infection Induces Genetic Instability of Nuclear and Mitochondrial DNA in Gastric Cells

Machado

Figueiredo

Touati

et al. 2009

Clinical Cancer Research

125

102

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Purpose: Helicobacter pylori is a major cause of gastric carcinoma. To investigate a possible link between bacterial infection and genetic instability of the host genome, we examined the effect of H. pylori infection on known cellular repair pathways in vitro and in vivo. Moreover, various types of genetic instabilities in the nuclear and mitochondrial DNA (mtDNA) were examined. Experimental Design: We observed the effects of H. pylori infection on a gastric cell line (AGS), on C57BL/6 mice, and on individuals with chronic gastritis. In AGS cells, the effect of H. pylori infection on base excision repair and mismatch repair (MMR) was analyzed by reverse transcription-PCR, Western blot, and activity assays. In mice, MMR expression was analyzed by reverse transcription-PCR and the CA repeat instabilities were examined by Mutation Detection Enhancement gel electrophoresis. Mutation spectra in AGS cells and chronic gastritis tissue were determined by PCR, single-stranded conformation polymorphism, and sequencing. H. pylori vacA and cagA genotyping was determined by multiplex PCR and reverse hybridization. Results: Following H. pylori infection, the activity and expression of base excision repair and MMR are down-regulated both in vitro and in vivo. Moreover, H. pylori induces genomic instability in nuclear CA repeats in mice and in mtDNA of AGS cells and chronic gastritis tissue, and this effect in mtDNA is associated with bacterial virulence. Conclusions: Our results suggest that H. pylori impairs central DNA repair mechanisms, inducing a transient mutator phenotype, rendering gastric epithelial cells vulnerable to the accumulation of genetic instability and thus contributing to gastric carcinogenesis in infected individuals.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Infection Induces Genetic Instability of Nuclear and Mitochondrial DNA in Gastric Cells

Machado

Figueiredo

Touati

et al. 2009

Clinical Cancer Research

125

102

View full text Add to dashboard Cite

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“…It has been widely accepted that intestinal-and diffuse-type gastric cancer differ with regards to age, gender and the process of carcinogenesis (13). The development of intestinal-type malignancy is a longer multistep process via gastric atrophy, intestinal metaplasia, dysplasia and ultimately intestinal-type carcinoma, which is initiated by H. pylori infection and by exposure to environmental toxins (14). TGFB1, as a regulator of inflammation, may be involved in this multistep process.…”

Section: Discussionmentioning

confidence: 99%

Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study

Zeng

Chen

et al. 2011

Oncology Letters

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Abstract.The transforming growth factor-β (TGFβ) pathway plays an important role in various types of human cancer. However, the role of TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms in gastric cancer is controversial. We aimed to investigate the associations between these polymorphisms and gastric cancer susceptibility, clinicopathological parameters and survival. A case-control study was conducted in 1,010 gastric cancer patients and 1,500 healthy controls. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. Compared with the TT genotype, the TGFB1 -509 C allele (CT/CC) was significantly associated with a reduced risk of gastric cancer (OR, 0.71; 95% CI, 0.58-0.87; P=0.001) and certain subtypes of gastric cancer including intestinal type (OR, 0.70; 95% CI, 0.57-0.87; P=0.001), poorly differentiated (OR, 0.67; 95% CI, 0.54-0.85; P=0.001) and stage TNM III+IV (OR, 0.73; 95% CI, 0.58-0.92; P=0.008). Compared with the TGFBR2 -875 GG genotype, carriers of the A allele (AA/AG) had a significantly decreased gastric cancer risk (OR, 0.58; 95% CI, P<0.001). A combination of the TGFB1 -509 C and TGFBR2 -875 A alleles was associated with a further decreased risk of gastric cancer (OR, 0.42; 95% CI, 0.32-0.57, P<0.001). No significant correlation was observed between polymorphisms and survival of gastric cancer patients. Our results suggest that both the TGFB1 -509 and TGFBR2 -875 polymorphisms contribute to a decreased gastric cancer risk. The TGFB1 -509 polymorphism affects certain subtypes of gastric cancer according to clinicopathological parameters. A combination of the TGFB1 -509 C and TGFBR2 -875 A alleles conferred a further decreased gastric cancer risk. These findings provide clues to the biological mechanisms that underline tumor heterogeneity.

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“…On the other hand, because the E-cadherin-catenin complex plays a critical role in the maintenance of nor mal tissue architecture, mutation of any of its components is believed to result in loss of cell-cell adhesion, thereby contributing to neoplasia development. In this respect, adenomatous polyposis coli (APC) gene abnormalities, found to be the "gate-keeping" event for the initiation of colorectal neoplasia, may lead to a disruption of normal cellcell adhesion through altered association with catenins and the cell adhesion molecule E-cadherin that binds catenins [39] . Translocation of the β-catenin protein, a key downstream effector of the Wnt signal transduction pathway, is frequently found in colorectal cancer.…”

Section: Chronic Radiation Colitis (Table 2)mentioning

confidence: 99%