The relationship between gastric carcinogenesis in rodent duodenogastric-reflux model and cyclooxygenase 2 (COX-2) expression, and the chemoprevention by a specific COX-2 inhibitor

本研究旨在探讨十二指肠胃反流致胃癌与环氧化酶2 （COX-2）表达的关系，并揭示特异性COX-2抑制剂美洛昔康（MLX）对胃癌发展的化学预防作用。将十二指肠胃反流手术大鼠分为两组，分别给予商业饲料（对照组）和含MLX （0.5 mg/Kg体重/天）的实验饲料（MLX组）。分别于术后20、30、40、50、60周处死。30分钟后，MLX组深囊性胃炎（GCP）癌前病变发生率明显低于对照组（32% vs 100%）。MLX组中腺瘤和腺癌的发生率也显著低于对照组（腺瘤为0%对52%，腺癌为0%对29%）。在整个实验期间，MLX组Ki-67标记指数均显著高于对照组。免疫组织化学检测COX-2不仅在GCP上皮、腺瘤和腺癌中表达，在间质中也有表达。两组间COX-2 mRNA表达量无显著差异，但MLX组PGE2产物水平高于对照组。上述结果提示，特异性COX-2抑制剂美洛昔康可抑制十二指肠胃反流致胃癌啮齿动物模型中GCP、腺瘤和腺癌的发生，推测该药物通过抑制COX-2抑制PGE2的产生，通过减少上皮细胞增殖来预防胃癌的发生。

The aims of this study are to investigate the relationship between gastric carcinogenesis by duodenogastric reflux and cyclooxygenase 2 (COX-2) expression, and to disclose the chemopreventive effect of a specific COX-2 inhibitor, meloxicam (MLX) to the development of gastric cancer. The rats surgically undergoing duodenogastric reflux were allocated to two groups, given commercial chow (Control group) and experimental chow containing MLX (0.5 mg/Kg body weight/day) (MLX group). The animals were sacrificed postoperatively at 20, 30, 40, 50, and 60 weeks. The incidence of gastritis cystica profunda (GCP), precancerous lesion, in the MLX group was significantly lower after the 30th weak than in the control group (32% vs 100%). The incidences of adenoma and adenocarcinoma in the MLX group were also significantly lower than in the control group (0% vs 52%, in adenoma, 0% vs 29%, in adenocarcinoma). The Ki-67 labeling index in the MLX group was significantly higher than in the control group through the whole experimental period. The COX-2 expression was immunohistochemically observed not only in the epithelium of GCP, adenoma and adenocarcinoma, but also in the stroma. The COX-2 mRNA expression did not differ between two groups but the level of PGE2 product in the MLX group was higher than in the control group. These results indicate that a specific COX-2 inhibitor, meloxicam, suppresses the development of GCP, adenoma and adenocarcinoma in the rodent model of gastric carcinogenesis by duodenogastric reflux, suspecting that the drug, which suppresses PGE2 production by COX-2 inhibition, prevents gastric carcinogenesis by reducing epithelial proliferation.