Gastrin-induced apoptosis contributes to carcinogenesis in the stomach
Department of Medicine, Division of Gastroenterology
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
Life Sciences | Medicine and Health Sciences
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.
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Citation: Lab Invest. 2006 Oct;86(10):1037-51. Epub 2006 Aug 7. Link to article on publisher's site
DOI of Published Version
Laboratory investigation; a journal of technical methods and pathology
Cui, Guanglin; Takaishi, Shigeo; Ai, Wandong; Betz, Kelly S.; Florholmen, Jon R.; Koh, Theodore J.; Houghton, JeanMarie; Pritchard, D. Mark; and Wang, Timothy C., "Gastrin-induced apoptosis contributes to carcinogenesis in the stomach" (2006). Open Access Articles. 1372.