Gastrin-induced apoptosis contributes to carcinogenesis in the stomach
Gastrin-induced apoptosis contributes to carcinogenesis in the stomach
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DOI：
10.1038/labinvest.3700462
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发表时间：
2006-10-01
影响因子：
5
通讯作者：
Wang, Timothy C.
中科院分区：
文献类型：
--
作者：
Cui, Guanglin;Takaishi, Shigeo;Wang, Timothy C.
INS-GAS小鼠的高胃泌素血症导致胃的加速癌变，但其机制尚未得到很好的定义。我们研究了胃泌素诱导的胃细胞凋亡在胃癌发生发展中的可能作用。我们检测了不同年龄的INS-GAS小鼠以及胃泌素-17（G-17）输注后的胃泌素缺陷（GAS-KO）小鼠中的细胞凋亡和Bcl-2家族蛋白的表达。此外，我们还研究了胃泌素/胆囊收缩素-2（CCK-2）受体拮抗剂YF 476和/或组胺H2（H-2）受体拮抗剂洛西丁对有或无猫螺杆菌（H.猫）感染。INS-GAS小鼠具有与年龄相关的Bax蛋白表达的增加和Bcl-2蛋白表达的减少，沿着腺和上皮细胞凋亡的增加。在GAS-KO小鼠中，8周的胃泌素输注导致Bax和Bcl-2表达改变的类似模式，随后是胃细胞凋亡。H. INS-GAS小鼠的猫感染导致细胞凋亡增加和萎缩的发展，而用YF 476和/或洛昔替丁处理强烈抑制细胞凋亡和萎缩。Fas表达RGM 1细胞的体外研究表明，单独的胃泌素刺激通过胃泌素/CCK-2受体直接诱导细胞凋亡，并与FasL刺激协同作用。提示胃泌素可诱导胃上皮细胞凋亡，参与胃癌的发生发展。
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.