Gastroenterology

Gastroenterology

Volume 125, Issue 4, October 2003, Pages 1125-1136
Gastroenterology

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

https://doi.org/10.1016/S0016-5085(03)01206-XGet rights and content

Abstract

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.

Section snippets

Bacterial strains

Experiments were performed with the cag+ vacA s1/m1 toxigenic H. pylori strain 60190 (ATCC no. 49503) or 2 previously described clinical H. pylori strains: B128 (cag+ vacA s1/m1 toxigenic) and J68 (cag− vacA s2/m2 nontoxigenic).38, 77 To examine the effects of specific H. pylori virulence components on MMP-7 expression, isogenic cagA, cagE, and vacA null mutants of strain 60190 that contain an inactivation cassette (aphA) conferring resistance to kanamycin77 were incubated with AGS gastric

H. pylori induces MMP-7 in AGS gastric epithelial cells

We first sought to determine if H. pylori altered MMP-7 expression in gastric cells; therefore, AGS cells were incubated with the H. pylori cag+ toxigenic strain 60190 and MMP-7 was quantified in 24-hour coculture supernatants by Western analysis. Compared with uninfected controls, strain 60190 significantly increased MMP-7 release an average of 7-fold over baseline (Figure 1).

We next examined whether contact with live H. pylori or exposure to secreted bacterial proteins was required for MMP-7

Discussion

Recent investigations into mechanisms that underlie H. pylori-induced gastric cancer have emphasized that disease risk involves specific and choreographed interactions between pathogen and host, which in turn are dependent on strain-specific bacterial factors and induced host effectors. H. pylori cag+ strains are disproportionately represented among persons who develop atrophic gastritis and distal gastric cancer,16, 17, 18, 19 and genes within the cag island are necessary for induction of

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    ☆

    Supported in part by National Institutes of Health grants CA 77955 and DK 58587, the F. D. H. N. Fiterman Foundation Award, and the Medical Research Service of the Department of Veterans Affairs.

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