title: Helicobacter pylori Activates Matrix Metalloproteinase 10 in Gastric Epithelial Cells via EGFR and ERK-mediated Pathways.
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.
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Costa
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology.
authors.forename: Rui M
authors.initials: RM
authors.lastname: Ferreira
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology.
authors.forename: Ines
authors.initials: I
authors.lastname: Pinto-Ribeiro
authors.affiliation: Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Ioanna S
authors.initials: IS
authors.lastname: Sougleri
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde Department of Pathology and Oncology, Faculty of Medicine INEB - Institute of Biomedical Engineering, University of Porto.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Oliveira
authors.affiliation: Department of Biology and CESAM, University of Aveiro, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Carreto
authors.affiliation: Department of Biology and CESAM, University of Aveiro, Portugal.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Santos
authors.affiliation: Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Dionyssios N
authors.initials: DN
authors.lastname: Sgouras
authors.affiliation: 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.
authors.forename: Fatima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology.
authors.forename: Marina
authors.initials: M
authors.lastname: Leite
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde Ipatimup - Institute of Molecular Pathology and Immunology Department of Pathology and Oncology, Faculty of Medicine.
authors.forename: Ceu
authors.initials: C
authors.lastname: Figueiredo
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology* / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism*; D008875:Middle Aged; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori; C512478:EGFR protein, human; D066246:ErbB Receptors; D048670:MAP Kinase Kinase 4; D053506:Matrix Metalloproteinase 10
keywords: CagA; EGFR; Helicobacter pylori; MMP-10; invasion