Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess β-catenin gene mutations and increases immunoreactivity for β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase
Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess β-catenin gene mutations and increases immunoreactivity for β-catenin, cyclooxygenase-2 and inducible nitric oxide synthase
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DOI：
10.1093/carcin/bgh292
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发表时间：
2005-01-01
期刊：
影响因子：
4.7
通讯作者：
Wakabayashi, K
中科院分区：
文献类型：
--
作者：
Tanaka, T;Suzuki, R;Wakabayashi, K
已知杂环胺是包括结肠在内的几个器官中的重要环境致癌物。本研究的目的是在短期内诱导结肠上皮恶性肿瘤，并分析诱导肿瘤中环氧化酶（考克斯）-2、诱导型一氧化氮合酶（iNOS）和β-catenin的表达及β-catenin基因突变。雄性Crj：CD-1小鼠单次i.g.给药（200 mg/kg体重）2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（PhIP）或2-氨基-3，8-二甲基咪唑并[4，5-f]喹喔啉（MeIQx），然后在饮用水中给药2%葡聚糖硫酸钠（DSS）一周。采用免疫组化法检测结肠上皮病变中β-catenin、考克斯-2和iNOS的表达，并采用单链构象多态性（SSCP）、限制性内切酶片段长度多态性（RFLP）和直接测序法检测结肠腺癌中β-catenin基因突变。在第16周，在接受PhIP和DSS的小鼠中出现了高发病率的结肠肿瘤伴异型增生病变，但在给予MeIQx和DSS的小鼠中仅出现了少数肿瘤。免疫组化结果显示，三种蛋白均呈阳性表达。PhIP和DSS诱导的所有七种腺癌都有突变。研究结果表明，DSS对PhIP引发的小鼠结肠癌发生具有强大的促肿瘤作用，这种小鼠模型可用于在短期内研究环境相关的结肠癌发生。
Heterocyclic amines are known to be important environmental carcinogens in several organs including the colon. The aim of this study was to induce colonic epithelial malignancies within a short-term period and analyze the expression of cycooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and beta-catenin, and mutations of beta-catenin gene in induced tumors. Male Crj: CD-1 mice were given a single i.g. administration (200 mg/kg body wt) of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) followed by 2% dextran sodium sulfate (DSS) in the drinking water for a week. The expression of beta-catenin, COX-2 and iNOS was immunohistochemically assessed in colonic epithelial lesions and the beta-catenin gene mutations in colonic adenocarcinomas induced were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. At week 16, a high incidence of colonic neoplasms with dysplastic lesions developed in mice that received PhIP and DSS, but only a few developed in those given MeIQx and DSS. Immunohistochemically, the adenocarcinomas induced were all positive for three proteins. All seven adenocarcinomas induced by PhIP and DSS have mutations. The findings suggest that DSS exerts powerful tumor-promoting effects on PhIP-initiated colon carcinogenesis in mice and this mouse model is useful for investigating environment-related colon carcinogenesis within a short-term period.