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Am J Physiol Gastrointest Liver Physiol 292: G1133-G1140, 2007. First published January 11, 2007; doi:10.1152/ajpgi.00526.2006
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HORMONES AND SIGNALING

Increased gastric expression of MMP-7 in hypergastrinemia and significance for epithelial-mesenchymal signaling

¹Physiological Laboratory, School of Biomedical Sciences, and ²Division of Gastroenterology, School of Clinical Sciences, University of Liverpool, Liverpool, United Kingdom; and ³Department of Medicine, Columbia University, Columbia, New York

Submitted 10 November 2006 ; accepted in final form 3 January 2007

Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Heliobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by -smooth muscle actin (-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and -SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-G_R and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.

matrix metalloproteinase-7; pernicious anemia; multiple endocrine neoplasia type 1; enterochromaffin-like cell carcinoid tumors

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