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J Infect Dis. 2016 Jun 1;213(11):1767-76. doi: 10.1093/infdis/jiw031. Epub 2016 Jan 21.

Helicobacter pylori Activates Matrix Metalloproteinase 10 in Gastric Epithelial Cells via EGFR and ERK-mediated Pathways.

Author information

1
i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology.
2
Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece.
3
i3S - Instituto de Investigação e Inovação em Saúde Department of Pathology and Oncology, Faculty of Medicine INEB - Institute of Biomedical Engineering, University of Porto.
4
Department of Biology and CESAM, University of Aveiro, Portugal.
5
i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology Department of Pathology and Oncology, Faculty of Medicine Department of Pathology, Centro Hospitalar São João, Porto.
6
i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology Department of Pathology and Oncology, Faculty of Medicine.

Abstract

Helicobacter pylori colonizes the human stomach and increases the risk for peptic ulcer disease and gastric carcinoma. H. pylori upregulates the expression and activity of several matrix metalloproteinases (MMPs) in cell lines and in the gastric mucosa. The aim of this study was to explore the mechanisms leading to upregulation of MMP10 in gastric epithelial cells induced by H. pylori Infection of gastric cells with H. pylori led to an increase in levels of MMP-10 messenger RNA, protein secretion, and activity. cagA knockout mutants or CagA phosphorylation-defective mutants failed to increase MMP10 expression. These results were confirmed in infection experiments with clinical isolates with known cagA status and in human gastric biopsy specimens. Treatment of cells with chemical inhibitors of the receptor tyrosine kinase EGFR and the kinase Src abrogated H. pylori-induced MMP10 expression. Inhibitors of ERK1/2 and JNK kinases abolished and significantly decreased H. pylori-induced MMP10 expression, respectively, whereas inhibition of the kinase p38 had no effect. Finally, inhibition of MMP10 expression by small interfering RNA led to a decrease in the gastric cell-invasive phenotype mediated by the infection. In conclusion, CagA-positive H. pylori strains stimulate MMP10 expression. MMP-10 modulation occurs via EGFR activation in a process that involves Src, ERK, and JNK pathways. MMP-10 may be implicated in H. pylori-mediated extracellular matrix remodeling.

KEYWORDS:

CagA; EGFR; Helicobacter pylori; MMP-10; invasion

PMID:
26802142
DOI:
10.1093/infdis/jiw031
[Indexed for MEDLINE]

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