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.

Gastrin activates autophagy and increases migration and survival of gastric adenocarcinoma cells

“…Others and we have previously reported increased migration and cell survival in response to gastrin [18, 24, 31]. In the present study, we assessed the influence of gastrin induced autophagy on both cell migration and cell survival.…”

Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

“…Twelve weeks was the maximum time permitted by the current toxicology studies in rat and dog [41]. We assessed efficacy by: counting the number of tumours; measuring the diameter of the largest tumour; measuring abundances of the gastrin-dependent genes, chromogranin A, histidine decarboxylase, matrix metalloproteinase-7, and plasminogen activator inhibitor-1 and -2 in tumour biopsies, all of which are increased in type 1 gastric NETs [42-45]; and measuring plasma CgA concentration. We assessed a range of potential tumour biomarkers, because there is no published evidence about the effect of a gastrin/CCK-2 receptor antagonist on gene expression in humans, and we wanted to prepare for future studies.…”

The stomach in health and disease

“…21) and a recent in vitro study showed that gastrin plays a key role in maintaining gastric stem cells. 22 Some of these effects arise as a result of the altered expression of proteins that regulate tissue remodelling including members of the matrix metalloproteinase, 23 tissue inhibitor of metalloproteinase 24 and urokinase plasminogen activator 25 families.…”