Gastrin-induced apoptosis contributes to carcinogenesis in the stomach.

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.

• Authors: Guanglin Cui, Shigeo Takaishi, Wandong Ai, Kelly S Betz, Jon Florholmen, Theodore J Koh, JeanMarie Houghton, D Mark Pritchard, Timothy C Wang
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 86 Issue 10 Pg. 1037-51 (Oct 2006) ISSN: 0023-6837 [Print] United States
• PMID: 16894354 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Gastrins
• Proto-Oncogene Proteins c-bcl-2
• Receptor, Cholecystokinin B
• Receptors, Histamine H2

Topics

• Animals
• Apoptosis (physiology)
• Atrophy (immunology, physiopathology)
• Disease Models, Animal
• Gastrins (physiology)
• Helicobacter Infections
• Helicobacter felis
• Male
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptor, Cholecystokinin B (physiology)
• Receptors, Histamine H2 (physiology)
• Stomach Neoplasms (microbiology, pathology, physiopathology)