title: Gastrin stimulates expression of plasminogen activator inhibitor-1 in gastric epithelial cells.
abstract: Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It is expressed in the stomach but the mechanisms controlling its expression there, and its biological role, are uncertain. We sought to define the role of gastrin in regulating PAI-1 expression and to determine the relevance for gastrin-stimulated cell migration and invasion. In gastric biopsies from subjects with elevated plasma gastrin, the abundances of PAI-1, urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNAs measured by quantitative PCR were increased compared with subjects with plasma concentrations in the reference range. In patients with hypergastrinemia due to autoimmune chronic atrophic gastritis, there was increased abundance of PAI-1, uPA, and uPAR mRNAs that was reduced by octreotide or antrectomy. Immunohistochemistry revealed localization of PAI-1 to parietal cells and enterochromaffin-like cells in micronodular neuroendocrine tumors in hypergastrinemic subjects. Transcriptional mechanisms were studied by using a PAI-1-luciferase promoter-reporter construct transfected into AGS-G(R) cells. There was time- and concentration-dependent increase of PAI-1-luciferase expression in response to gastrin that was reversed by inhibitors of the PKC and MAPK pathways. In Boyden chamber assays, recombinant PAI-1 inhibited gastrin-stimulated AGS-G(R) cell migration and invasion, and small interfering RNA treatment increased responses to gastrin. We conclude that elevated plasma gastrin concentrations are associated with increased expression of gastric PAI-1, which may act to restrain gastrin-stimulated cell migration and invasion.
authors.affiliation: Physiological Laboratory, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Nørsett
authors.forename: Islay
authors.initials: I
authors.lastname: Steele
authors.forename: Cedric
authors.initials: C
authors.lastname: Duval
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sammut
authors.forename: Senthil V M
authors.initials: SV
authors.lastname: Murugesan
authors.forename: Susan
authors.initials: S
authors.lastname: Kenny
authors.forename: Lucille
authors.initials: L
authors.lastname: Rainbow
authors.forename: Rod
authors.initials: R
authors.lastname: Dimaline
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Dockray
authors.forename: D Mark
authors.initials: DM
authors.lastname: Pritchard
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
mesh_terms: D019861:Enterochromaffin-like Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005755:Gastrins / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D015282:Octreotide; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis; D013270:Stomach / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
chemical_list: D005755:Gastrins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D015282:Octreotide