Helicobacter pylori activates matrix metalloproteinase 10 in gastric epithelial cells via EGFR and ERK-mediated pathways

Angela M. Costa, Rui M. Ferreira, Ines Pinto-Ribeiro, Ioanna S. Sougleri, Maria J. Oliveira, Laura Carreto, Manuel A. Santos, Dionyssios N. Sgouras, Fatima Carneiro, Marina Leite, Ceu Figueiredo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1767-1776
Number of pages10
JournalThe Journal of infectious diseases
Volume213
Issue number11
DOIs
Publication statusPublished - 1 Jun 2016
Externally publishedYes

Keywords

  • CagA
  • EGFR
  • Helicobacter pylori
  • Invasion
  • MMP-10

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