title: PAI-1 deficiency increases the trophic effects of hypergastrinemia in the gastric corpus mucosa.
abstract: The gastric hormone gastrin plays a role in organizing the gastric mucosa. Gastrin also regulates the expression of genes that have important actions in extracellular matrix modelling, including plasminogen activator inhibitor (PAI)-1 which is part of the urokinase plasminogen activator (uPA) system. The uPA system (including PAI-1) is associated with cancer progression, fibrosis and thrombosis. Its biological role in the stomach and molecular mechanisms of action are not well understood. The aim of this study was to examine the effect of PAI-1 on the trophic changes observed in gastric corpus mucosa in hypergastrinemia using PAI-1 and/or HK-ATPase beta subunit knockout (KO) mice. HK-ATPase beta subunit KO mice were used as a model of hypergastrinemia. In 12 month old female mice, intragastric acidity and plasma gastrin were measured. The stomachs were examined for macroscopic and histological changes. In mice null for both PAI-1 and HK-ATPase beta (double KO), there was exaggerated hypergastrinemia, increased stomach weight and corpus mucosal thickness, and more pronounced trophic and architectural changes in the corpus compared with HK-ATPase beta KO mice. Genome-wide microarray expression data for the gastric corpus mucosa showed a distinct gene expression profile for the HK-ATPase beta KO mice; moreover, enrichment analysis revealed changes in expression of genes regulating intracellular processes including cytoskeleton remodelling, cell adhesion, signal transduction and epithelial-to-mesenchymal transition (EMT). Genes differentially expressed in the double KO compared with HK-ATPase beta KO mice included the transcription factor Barx2 and the chromatin remodeler gene Tet2, which may be involved in both normal gastric physiology and development of gastric cancer. Based on the present data, we suggest that PAI-1 plays a role in maintaining gastric mucosal organization in hypergastrinemia.
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway; Department of Gastroenterology and Hepatology, St. Olav's University Hospital, Trondheim, Norway. Electronic address: reidar.fossmark@ntnu.no.
authors.forename: Reidar
authors.initials: R
authors.lastname: Fossmark
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway. Electronic address: shalini.rao@ntnu.no.
authors.forename: Shalini
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway; Department of Pathology, St. Olav's University Hospital, Trondheim, Norway. Electronic address: patricia.mjones@ntnu.no.
authors.forename: Patricia
authors.initials: P
authors.lastname: Mjønes
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway. Electronic address: bjorn.munkvold@ntnu.no.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Munkvold
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway. Electronic address: arnar.flatberg@ntnu.no.
authors.forename: Arnar
authors.initials: A
authors.lastname: Flatberg
authors.affiliation: Department of Cell and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. Electronic address: a.varro@liverpool.ac.uk.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway. Electronic address: liv.thommesen@ntnu.no.
authors.forename: Liv
authors.initials: L
authors.lastname: Thommesen
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway; The Central Norway Regional Health Authority, Trondheim, Norway. Electronic address: kristin.norsett@ntnu.no.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Nørsett
mesh_terms: D000818:Animals; D019861:Enterochromaffin-like Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology* / Q000473:pathology; D005755:Gastrins / Q000097:blood*; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011706:Pyloric Antrum / Q000201:enzymology / Q000473:pathology; D058258:Serpin E2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D005755:Gastrins; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D017506:H(+)-K(+)-Exchanging ATPase
keywords: Gastric mucosa; Gastric proton pump; Gastrin; Plasminogen activator inhibitor-1