Gastrin-induced apoptosis contributes to carcinogenesis in the stomach.
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.
Cui
Guanglin
G
Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Takaishi
Shigeo
S
Ai
Wandong
W
Betz
Kelly S
KS
Florholmen
Jon
J
Koh
Theodore J
TJ
Houghton
JeanMarie
J
Pritchard
D Mark
DM
Wang
Timothy C
TC
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001284:Atrophy / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005755:Gastrins / Q000502:physiology*; D016481:Helicobacter Infections; D044922:Helicobacter felis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000502:physiology*; D011970:Receptors, Histamine H2 / Q000502:physiology*; D013274:Stomach Neoplasms / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*
D005755:Gastrins; D019253:Proto-Oncogene Proteins c-bcl-2; D043887:Receptor, Cholecystokinin B; D011970:Receptors, Histamine H2