Helicobacter pylori strain-selective induction of matrix metalloproteinase-7 in vitro and within gastric mucosa.
OBJECTIVE
Helicobacter pylori strains that possess the cag pathogenicity island (cag(+)) augment the risk for distal gastric cancer. Matrix metalloproteinase (MMP)-7, an epithelial cell-derived MMP that is induced by bacterial contact, is overexpressed within human gastric adenocarcinoma specimens and enhances tumor formation in rodents. We determined whether H. pylori alters MMP-7 expression and investigated the molecular pathways required for these events.


METHODS
MMP-7 was detected in human gastric mucosa by immunohistochemistry and in H. pylori/AGS gastric epithelial cell coculture supernatants by Western analysis. AGS cells were cocultured with wild-type H. pylori, or isogenic cagA(-), cagE(-), or vacA(-) mutants, in the absence or presence of inhibitors of nuclear factor kappaB activation, p38, or extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase.


RESULTS
H. pylori cag(+) strains increased MMP-7 expression in AGS cells 5-7-fold, whereas cag(-) isolates had no effect. Inactivation of cagE, but not cagA or vacA, completely attenuated induction of MMP-7, and inhibition of ERK 1/2 decreased MMP-7 production. In vivo, MMP-7 was expressed in gastric epithelial cells in specimens from 80% of cag(+)-colonized persons but in none of the cag(-) or uninfected subjects.


CONCLUSIONS
H. pylori cag(+) strains enhance levels of MMP-7 within inflamed mucosa. In vitro, cag(+) isolates selectively induce MMP-7, and this is dependent on activation of ERK 1/2 by specific components within the cag island. Differential induction of MMP-7 by H. pylori cag(+) isolates may explain in part the augmentation in gastric cancer risk associated with these strains.
D002478:Cells, Cultured; D005753:Gastric Mucosa / Q000166:cytology / Q000201:enzymology / Q000382:microbiology*; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000145:classification / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013045:Species Specificity; D013274:Stomach Neoplasms / Q000382:microbiology; D015854:Up-Regulation
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D012697:Serine Endopeptidases; C054542:chymostatin-sensitive angiotensin II-generating enzyme; D020783:Matrix Metalloproteinase 7