Celecoxib inhibits Cdx2 expression and prevents gastric cancer in Helicobacter pylori-infected Mongolian gerbils
Celecoxib inhibits Cdx2 expression and prevents gastric cancer in Helicobacter pylori-infected Mongolian gerbils
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DOI：
10.1159/000100503
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发表时间：
2006-01-01
期刊：
影响因子：
3.2
通讯作者：
Sakamoto, Choitsu
中科院分区：
文献类型：
--
作者：
Futagami, Seiji;Suzuki, Kenji;Sakamoto, Choitsu
背景/目的：本研究的目的是观察在肠化生出现之前给予选择性COX-2抑制剂塞来昔布是否可以预防幽门螺杆菌感染的蒙古沙鼠胃癌的发展。方法：将52只沙鼠分为3组，每2周给予5次n -甲基-n -亚硝基脲（MNU; 30ppm）。第12周，第2组（n = 20）和第3组（n = 22）沙鼠注射幽门螺杆菌，第1组（n = 10）对照组只注射布鲁氏菌肉汤。此外，在幽门螺杆菌接种7周后，第19周，3组沙鼠也在其饮食中给予塞来昔布（1500 ppm） 36周的给药疗程。在第54周通过组织学分析确定胃腺癌的发生率。检测各组COX-2、Cdx2蛋白表达及COX活性。采用免疫组化半定量法检测肠化生程度、Cdx2、MUC2表达及细胞凋亡指数。结果：1组胃腺癌发生率为0% (0/10)；2组为65%(13/20)，3组为23% (5/22),p < 0.05。持续给药塞来昔布显著降低幽门螺旋杆菌感染沙鼠COX活性、COX-2蛋白表达、Cdx2和MUC2蛋白免疫反应性以及阿利新蓝周期性酸-希夫阳性肠化生程度。塞来昔布也能诱导沙鼠细胞凋亡。Western blot分析显示，Cdx2在3组沙鼠中表达明显抑制。结论：在肠化生首次出现之前，及时给药塞来昔布通过抑制mnu预处理的幽门螺旋杆菌感染蒙古沙鼠的Cdx2表达，破坏肠化生向胃癌的进展，从而预防胃癌的发生。版权所有(c) 2006 S. Karger AG，巴塞尔。
Background/Aim: The aim of this study was to see whether administration of celecoxib, a selective COX-2 inhibitor, prior to the appearance of intestinal metaplasia could prevent the development of gastric cancer in Helicobacter pylori-infected Mongolian gerbils. Methods: Fifty-two Mongolian gerbils were divided into 3 groups and given 5 biweekly doses of N-methyl-N-nitrosourea (MNU; 30 ppm). At week 12, group 2 (n = 20) and group 3 ( n = 22) gerbils were then given an injection of H. pylori, while group 1 controls ( n = 10) received Brucella broth alone. In addition, 7 weeks after H. pylori inoculation, at week 19, group 3 gerbils also received a 36-week administration course of celecoxib ( 1,500 ppm) in their diet. The incidence of gastric adenocarcinoma was determined at week 54 by histological analysis. COX-2 and Cdx2 protein expression and COX activity were evaluated for each group. The extent of intestinal metaplasia, Cdx2 and MUC2 expression, and the apoptotic index were evaluated semi-quantitatively by immunohistochemistry. Results: The incidence of gastric adenocarcinoma was: group 1, 0% (0/10); group 2, 65% (13/20), and group 3, 23% (5/22; p < 0.05). Continuous celecoxib administration significantly reduced COX activity and COX-2 protein expression, Cdx2 and MUC2 protein immunoreactivity, and the extent of Alcian blue periodic acid-Schiff-positive intestinal metaplasia in H. pylori-infected gerbils. Celecoxib also induced apoptosis in these gerbils. Significant inhibition of Cdx2 expression in group 3 gerbils was also shown by Western blot analysis. Conclusions: Prior to the first appearance of intestinal metaplasia, timely administration of celecoxib prevents gastric cancer occurrence by disrupting the progression of intestinal metaplasia into gastric carcinoma through its inhibition of Cdx2 expression in MNU-pretreated H. pylori-infected Mongolian gerbils. Copyright (c) 2006 S. Karger AG, Basel.