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合酶-2(COX-2)表达的关系，以及特异性COX-2抑制剂美洛昔康(MLX)对胃癌发生的化学预防作用。将接受十二指肠胃反流手术的大鼠分为两组，分别给予商品饲料(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周处死动物。30天后MLX组癌前病变--深囊性胃炎(GCP)的发生率明显低于对照组(32%比100%)。MLX组腺瘤和腺癌的发生率也显著低于对照组(腺瘤为0%比52%，腺癌为0%比29%)。在整个实验过程中，MLX组Ki-67标记指数均显著高于对照组。免疫组织化学染色显示，COX-2不仅在GCP、腺瘤和腺癌上皮细胞中表达，而且在间质中也有表达。两组间COX-2mRNA表达差异无统计学意义，但MLX组PGE2产物表达水平高于对照组。这些结果表明，在十二指肠胃反流致胃癌的啮齿动物模型中，特异性的COX-2抑制剂美洛昔康可以抑制GCP、腺瘤和腺癌的发展，并怀疑该药物通过抑制COX-2抑制PGE2的产生，通过减少上皮细胞的增殖来防止胃癌的发生。

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.