title: Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression.
abstract: The gastric hormone gastrin regulates the organization of the gastric epithelium, but the cellular control mechanisms are yet unknown. Epithelial remodelling typically involves extracellular proteolysis mediated by the matrix metalloproteinases (MMPs). Since a gene-array analysis of the gastric cancer cell line AGS-G(R) suggested that gastrin increased MMP-9 expression, we examined the control of MMP-9 expression by gastrin. Gelatin zymography confirmed gastrin induction of MMP-9 in AGS-G(R) cells, but showed a small inhibition of MMP-2. Immunocytochemical studies showed that MMP-9 was localized to vesicles that appeared to traffic along the processes that were extended in response to gastrin. Gastrin stimulated the invasion of AGS-G(R) cells through artificial basement membrane, which was reduced by an inhibitor of MMP-2/-9. There was also an increase in MMP-9 in the stomach of patients with elevated plasma gastrin and multiple-endocrine neoplasia type 1 (MEN-1) syndrome, suggesting in vivo regulation of MMP-9 expression by gastrin. Finally, we showed that the expression of 1.9 kb of human MMP-9 gene promoter coupled with luciferase (MMP-9-luc) was increased 7.65+/-1.2-fold by gastrin, via a pathway which includes stimulation of protein kinase C, and activation of Raf and the mitogen-activated protein (MAP) kinase pathway. The tumour suppressor menin (which is mutated in MEN-1 syndrome) inhibited the expression of MMP-9-luc by gastrin. These results suggest that gastrin increases MMP-9 expression, which is associated with increased invasion, and this is a putative mechanism regulating remodelling of the gastric epithelium.
authors.affiliation: Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, U.K.
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Wroblewski
authors.forename: David M
authors.initials: DM
authors.lastname: Pritchard
authors.forename: Stuart
authors.initials: S
authors.lastname: Carter
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
mesh_terms: D000818:Animals; D002276:Carcinoid Tumor / Q000201:enzymology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D005755:Gastrins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005755:Gastrins; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D020780:Matrix Metalloproteinase 9