Title

Gastrin-induced apoptosis contributes to carcinogenesis in the stomach

UMMS Affiliation

Department of Medicine, Division of Gastroenterology

Publication Date

2006-08-09

Document Type

Article

Subjects

Animals; Apoptosis; Atrophy; Disease Models, Animal; Gastrins; Helicobacter Infections; Helicobacter felis; Male; Mice; Mice, Knockout; Proto-Oncogene Proteins c-bcl-2; Receptor, Cholecystokinin B; Receptors, Histamine H2; Stomach Neoplasms

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Hypergastrinemia in INS-GAS mice leads to accelerated carcinogenesis of the stomach, but the mechanisms have not been well defined. We investigated the possible role of gastrin-induced gastric cell apoptosis in the development of gastric cancer. We examined apoptosis and the expression of Bcl-2 family proteins in INS-GAS mice of different ages, as well as in gastrin-deficient (GAS-KO) mice after gastrin-17 (G-17) infusion. In addition, we studied the effects of the gastrin/cholecystokinin-2 (CCK-2) receptor antagonist YF476 and/or histamine H2 (H-2) receptor antagonist loxtidine on apoptosis and atrophy in INS-GAS mice with or without Helicobacter felis (H. felis) infection. INS-GAS mice had age-associated increases in Bax protein expression and decreases in Bcl-2 protein expression, along with increased glandular and epithelial cell apoptosis. At 8-week gastrin infusions in GAS-KO mice resulted in a similar pattern of altered Bax and Bcl-2 expression, followed by gastric cell apoptosis. H. felis infection of INS-GAS mice led to increased apoptosis and the development of atrophy, whereas treatment with either YF476 and/or loxtidine strongly inhibited both apoptosis and atrophy. In vitro studies with Fas-expressing RGM1 cells showed that gastrin stimulation alone directly induced apoptosis via gastrin/CCK-2 receptor and synergized with FasL stimulation. These results indicate that gastrin can induce apoptosis in gastric epithelial cells and contribute to the development of gastric carcinogenesis.

DOI of Published Version

10.1038/labinvest.3700462

Source

Lab Invest. 2006 Oct;86(10):1037-51. Epub 2006 Aug 7. Link to article on publisher's site

Journal/Book/Conference Title

Laboratory investigation; a journal of technical methods and pathology

Related Resources

Link to Article in PubMed

PubMed ID

16894354

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