Helicobacter pylori Activates Calpain via Toll-Like Receptor 2 To Disrupt Adherens Junctions in Human Gastric Epithelial Cells

O'Connor, Pamela M. J.; Lapointe, Tamia K.; Jackson, Shannon; Beck, Paul L.; Jones, Nicola L.; Buret, André G.

doi:10.1128/iai.05109-11

Cited by 40 publications

(27 citation statements)

References 54 publications

(66 reference statements)

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“…Studies conducted by us, as well as previous reports showed that H. pylori reduces E-cadherin protein levels and disrupts the adherens junctions [14, 15]. Exposure to H. pylori also induced p38 and JNK kinases.…”

Section: Discussionsupporting

confidence: 66%

“…E-cadherin is a component of the adherens junctions that regulates cell-cell adhesion, intracellular signaling, cell polarity, and proliferation [10, 13]. H. pylori infection has shown to acutely cleave E-cadherin and disrupt the adherens junctions [14, 15]. H. pylori infection can also decrease expression of E-cadherin by promoting hypermethylation of the E-cadherin gene ( CDH1 ) that can be reversed by eradication of the bacteria [16–18].…”

Section: Introductionmentioning

confidence: 99%

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Helicobacter pylori bacteria alter the p53 stress response via Erk-HDM2 pathway

et al. 2015

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H. pylori infection is the strongest known risk factor for gastric cancer. Inhibition of host tumor suppressor mechanisms by the bacteria underlies the development of this disease. Among the tumor suppressors affected by H. pylori are p53 and E-cadherin, which inhibition has been shown to increase the risk of gastric cancer. In this report, we investigated the interaction between E-cadherin and p53 in H. pylori-infected cells. We found that downregulation of E-cadherin leads to cellular stress and activation of p53. In the setting of H. pylori infection, this mechanism, however, is disrupted. We found that although co-culture of gastric epithelial cells with H. pylori led to downregulation of E-cadherin and cellular stress, it resulted in inhibition of p53, which is mediated by intracellular Erk kinases and HDM2 protein induced by H. pylori. Experimental inhibition of HDM2/p53 interactions restored p53 activity, and decreased survival of infected cells. Collectively, our results revealed that regulation of p53 and E-cadherin is tightly linked through the p53 stress response mechanism that is inhibited by H. pylori via activation of Erk1/2-HDM2-p53 pathway leading to survival of damaged cells. This might be advantageous to the bacteria but may increase the cancer risk.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori bacteria alter the p53 stress response via Erk-HDM2 pathway

et al. 2015

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“…CagA also inhibits the polarity regulator PAR1b/MARK2 kinase, which causes a loss of epithelial cell polarity and plays a role in the disruption of normal epithelial architecture [Hatakeyama, 2008]. Another hypothesized mechanism for disruption of adherens junctions within gastric epithelial cells is a H. pylori surface protein‐TLR (toll‐like receptor) 2‐induced activation of the protease calpain, which cleaves E‐cadherin and allows for increased β‐catenin signaling [O'Connor et al, 2011].…”

Section: Pathogenicity Of H Pylorimentioning

confidence: 99%

Role of the Helicobacter pylori‐Induced inflammatory response in the development of gastric cancer

Lamb

Chen

2013

J of Cellular Biochemistry

170

134

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H. pylori infection causes chronic gastritis and peptic ulceration and is the strongest risk factor for the development of gastric cancer. The pathogenesis of H. pylori is believed to be associated with infection-initiated chronic gastritis, which is characterized by enhanced expression of many inflammatory genes. H. pylori utilizes various virulence factors, targeting different cellular proteins, to modulate the host inflammatory response. In this review, we explore the many different ways by which H. pylori initiates inflammation, leveling many “hits” on the gastric mucosa which can lead to the development of cancer. We also discuss some recent findings in understanding the pathogen-host interactions and the role of transcription factor NF-κB in H. pylori-induced inflammation.

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“…It will be of interest to expand this observation to larger cohorts, and especially with longitudinal follow-up. H. pylori -induced calpain activation results in cleavage of E-cadherin to produce a truncated form and induce relocalization of E-cadherin and β-catenin and inhibition of TLR2 prevented H. pylori -induced calpain activation and adherens junctions (AJ) disassembly 41 . O′Connor suggested H. pylori activates calpain via TLR2 to disrupt gastric epithelial AJ structure—in turn, the disruption of AJ structure favors severe disease 41 .…”

Section: Discussionmentioning

confidence: 99%

Antral atrophy, intestinal metaplasia, and preneoplastic markers in Mexican children with Helicobacter pylori–positive and Helicobacter pylori–negative gastritis

Villarreal-Calderon

Luévano-González

Aragón-Flores

et al. 2014

Annals of Diagnostic Pathology

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Chronic inflammation and infection are major risk factors for gastric carcinogenesis in adults. As chronic gastritis is common in Mexican children, diagnosis of Helicobacter pylori and other causes of gastritis are critical for the identification of children who would benefit from closer surveillance. Antral biopsies from 82 Mexican children (mean age 8.3±4.8y) with chronic gastritis (36 H. pylori +, 46 H. pylori -) were examined for gastritis activity, atrophy, intestinal metaplasia, and immunohistochemical expression of gastric carcinogenesis biomarkers CDX2, ephrin type-B receptor 4, matrix metalloproteinase 3 (MMP3), macrophage migration inhibitory factor (MIF), p53, β-catenin, and E-cadherin. Atrophy was diagnosed in 7/82 (9%) and intestinal metaplasia in 5/82 (6%) by routine histology, while 6 (7%) additional children (3 H. pylori +) exhibited aberrant CDX2 expression without intestinal metaplasia. Significant positive correlations were seen between EphB4, MMP3, and MIF (p<0.0001). Atrophy and follicular pathology were more frequent in H. pylori + biopsies (p<0.0001), while intestinal metaplasia and CDX2 expression showed no significant correlation with H. pylori status. Antral biopsies demonstrating atrophy, intestinal metaplasia, and/or aberrant CDX2 expression were seen in 21.95 % (18/82) of the children, potentially identifying those who would benefit from closer surveillance and preventive dietary strategies. Biomarkers CDX2, EphB4, MMP3, and MIF may be useful in the work-up of pediatric gastritis.

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Helicobacter pylori Activates Calpain via Toll-Like Receptor 2 To Disrupt Adherens Junctions in Human Gastric Epithelial Cells

Cited by 40 publications

References 54 publications

Helicobacter pylori bacteria alter the p53 stress response via Erk-HDM2 pathway

Helicobacter pylori bacteria alter the p53 stress response via Erk-HDM2 pathway

Role of the Helicobacter pylori‐Induced inflammatory response in the development of gastric cancer

Antral atrophy, intestinal metaplasia, and preneoplastic markers in Mexican children with Helicobacter pylori–positive and Helicobacter pylori–negative gastritis

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