STOMACH

Helicobacter pylori upregulates matrilysin (MMP-7) in epithelial cells in vivo and in vitro in a Cag dependent manner

J R Bebb¹, D P Letley¹, R J Thomas¹, F Aviles¹, H M Collins², S A Watson², N M Hand³, A Zaitoun³, J C Atherton¹

¹ Division of Gastroenterology and Institute of Infections, Immunity, and Inflammation, University Hospital, Nottingham, UK
² Academic Unit of Cancer Studies, University Hospital, Nottingham, UK
³ Histopathology Department, University Hospital, Nottingham, UK

Correspondence to:
Correspondence to:
Professor J C Atherton, Division of Gastroenterology, University Hospital, Nottingham NG12 2NH, UK;
john.atherton{at}nottingham.ac.uk

Background and aims: Matrix metalloproteinase-7 (MMP-7) is important in normal and pathological remodelling of epithelial-matrix interactions, and is upregulated in gastric cancer. Helicobacter pylori infection is the first stage in gastric carcinogenesis, and therefore our aim was to determine if H pylori upregulated gastric MMP-7 expression and if this was affected by strain virulence.

Methods: We took gastric biopsy specimens at endoscopy from H pylori infected (n = 17) and uninfected (n = 18) patients and assessed MMP-7 expression by ELISA, real time polymerase chain reaction (PCR), and immunohistochemistry (concentrating on epithelial cells in the proliferative zone). We PCR typed H pylori for cagE and vacA. We performed H pylori/cell line coculture studies with wild-type pathogenic and non-pathogenic H pylori strains and with CagE^- and VacA^- isogenic mutants.

Results: Gastric biopsy specimens from H pylori+ patients expressed higher levels of MMP-7 at the protein and mRNA levels in the antrum and corpus (for example, by ELISA: H pylori+ 0.182 OD units vH pylori- 0.059; p = 0.009 antrum). Epithelial cells from H pylori+ patients stained more intensely for MMP-7 than those from uninfected patients, including in the proliferative zone containing pluripotent cells (p<0.03 antrum, p<0.04 body). Upregulation of MMP-7 in epithelial cells was confirmed at the protein and mRNA levels by H pylori/cell line coculture. These experiments also showed that MMP-7 upregulation was dependent on an intact H pyloricag pathogenicity island but not on the vacuolating cytotoxin.

Conclusion: We speculate that increased expression of MMP-7 in H pylori gastritis may contribute to gastric carcinogenesis.

Keywords: Helicobacter pylori; matrix metalloproteinase-7; cag pathogenicity island; gastric cancer

Abbreviations: MMPs, matrix metalloproteinases; MMP-7, matrix metalloproteinase-7 (matrilysin); FCS, fetal calf serum; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Ct, threshold cycle; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; ELISA, enzyme linked immunosorbent assay; TNF-, tumour necrosis factor

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