Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model
Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model
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DOI：
10.1093/carcin/22.11.1831
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发表时间：
2001-11-01
期刊：
影响因子：
4.7
通讯作者：
Lupton, JR
中科院分区：
文献类型：
--
作者：
Hong, MY;Chapkin, RS;Lupton, JR
现在人们普遍认为近端和远端结肠癌的病因可能不同，从而促使人们重新关注肿瘤发展的解剖部位特异性分子机制。使用雄性Sprague-Dawley大鼠的2 × 2 × 2析因设计（玉米油、鱼油;果胶、纤维素;加上或减去氧化偶氮甲烷注射），我们发现近端与远端肿瘤发生率的差异大于2倍（P < 0.001）（近端/远端比：玉米油，2.25;鱼油，2.61）。本研究的目的是确定在我们的模型系统中，近端肿瘤与远端肿瘤的程度较高是否可以通过这两个部位之间在初始DNA损伤、对该损伤的反应或饮食对一个部位而不是另一个部位的影响的差异来解释。通过O-6-甲基鸟嘌呤加合物的定量免疫组织化学评估DNA损伤;通过测量O-6-甲基鸟嘌呤-DNA烷基转移酶来确定修复，并通过测量靶向细胞凋亡来确定去除。虽然两个部位的总体初始DNA损伤相似，但在远端结肠中有更高的修复蛋白表达（P < 0.001）和更高程度的靶向凋亡（P < 0.0001）。食用鱼油的大鼠远端结肠的DNA损伤也有所减少。总之，这些结果表明，远端结肠中较低的肿瘤发生率可能是与近端结肠相比，远端结肠处理初始DNA损伤的能力的结果。因此，确定肿瘤发展中的位点特异性机制是重要的，因为可能需要不同的策略来保护不同位点的癌症。
There is now general agreement that the etiology of proximal and distal colon cancers may differ, thus prompting renewed interest in understanding anatomical site-specific molecular mechanisms of tumor development. Using a 2 X 2 X 2 factorial design with male Sprague-Dawley rats (corn oil, fish oil; pectin, cellulose; plus or minus azoxymethane injection) we found a greater than 2-fold difference (P < 0.001) in tumor incidence proximally versus distally (prox/dist ratio: corn oil, 2.25; fish oil, 2.61). The purpose of the present study was to determine if the higher degree of proximal versus distal tumors in our model system could be accounted for by differences between these two sites in initial DNA damage, response to that damage or an effect of diet at one site but not the other. DNA damage was assessed by quantitative inmumohistochemistry of O-6-methylguanine adducts; repair by measurement of O-6-methylguanine-DNA alkyltransferase and removal was determined by measurement of targeted apoptosis. Although overall initial DNA damage was similar at both sites, in the distal colon there was a greater expression of repair protein (P < 0.001) and a greater degree of targeted apoptosis (P < 0.0001). There was also a reduction in DNA damage in the distal colon of rats consuming fish oil. Together, these results suggest that the lower tumor incidence in the distal colon may be a result of the capacity to deal with initial DNA damage by the distal colon, as compared with the proximal colon. Therefore, the determination of site-specific mechanisms in tumor development is important because distinct strategies may be required to protect against cancer at different sites.