Helicobacter pylori strain-selective induction of matrix metalloproteinase-7 in vitro and within gastric mucosa

Background & Aims: 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 κB 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.