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