Gastrin stimulates MMP-1 expression in gastric epithelial cells: putative role in gastric epithelial cell migration

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2015-07, Vol.309 (2), p.G78-G86
• Main Authors: Kumar, J Dinesh, Steele, Islay, Moore, Andrew R, Murugesan, Senthil V, Rakonczay, Zoltan, Venglovecz, Viktoria, Pritchard, D Mark, Dimaline, Rodney, Tiszlavicz, Laszlo, Varro, Andrea, Dockray, Graham J
• Format: Article
• Language: English
• Subjects: Animals; Bioassays; Case-Control Studies; Cell Movement - drug effects; Cells, Cultured; Cellular biology; Epithelial Cells - drug effects; Epithelial Cells - enzymology; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Gastrins - blood; Gastrins - genetics; Gastrins - metabolism; Hormones; Hormones, Neurotransmitters, Growth Factors, Receptors, and Signaling; Human subjects; Humans; Kinases; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Protein expression; Protein Kinase C - metabolism; Proton Pump Inhibitors - pharmacology; Rats; RNA, Messenger - metabolism; Signal Transduction; Transfection; Up-Regulation
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00084.2015

The pyloric antral hormone gastrin plays a role in remodeling of the gastric epithelium, but the specific targets of gastrin that mediate these effects are poorly understood. Glandular epithelial cells of the gastric corpus express matrix metalloproteinase (MMP)-1, which is a potential determinant of tissue remodeling; some of these cells express the CCK-2 receptor at which gastrin acts. We have now examined the hypothesis that gastrin stimulates expression of MMP-1 in the stomach. We determined MMP-1 transcript abundance in gastric mucosal biopsies from Helicobacter pylori negative human subjects with normal gastric mucosal histology, who had a range of serum gastrin concentrations due in part to treatment with proton pump inhibitors (PPI). The effects of gastrin were studied on gastric epithelial AGS-GR cells using Western blot and migration assays. In human subjects with increased serum gastrin due to PPI usage, MMP-1 transcript abundance was increased 2-fold; there was also increased MMP-7 transcript abundance but not MMP-3. In Western blots, gastrin increased proMMP-1 abundance, as well that of a minor band corresponding to active MMP-1, in the media of AGS-GR cells, and the response was mediated by protein kinase C and p42/44 MAP kinase. There was also increased MMP-1 enzyme activity. Gastrin-stimulated AGS-GR cell migration in both scratch wound and Boyden chamber assays was inhibited by MMP-1 immunoneutralization. We conclude that MMP-1 expression is a target of gastrin implicated in mucosal remodeling.