Hong M Y, Chapkin R S, Morris J S, Wang N, Carroll R J, Turner N D, Chang W C, Davidson L A, Lupton J R
Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2471, USA.
Carcinogenesis. 2001 Nov;22(11):1831-5. doi: 10.1093/carcin/22.11.1831.
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 2x2x2 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 immunohistochemistry 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.
目前人们普遍认为，近端结肠癌和远端结肠癌的病因可能不同，这促使人们重新关注了解肿瘤发生的解剖部位特异性分子机制。我们采用2×2×2析因设计，对雄性斯普拉格-道利大鼠（玉米油、鱼油；果胶、纤维素；加或不加氧化偶氮甲烷注射）进行研究，发现近端与远端的肿瘤发生率存在2倍以上的差异（P < 0.001）（近端/远端比率：玉米油组为2.25；鱼油组为2.61）。本研究的目的是确定在我们的模型系统中，近端肿瘤发生率高于远端肿瘤发生率是否可归因于这两个部位在初始DNA损伤、对该损伤的反应方面存在差异，或者是饮食对一个部位有影响而对另一个部位没有影响。通过对O(6)-甲基鸟嘌呤加合物进行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烷基转移酶来评估修复情况，并通过测量靶向凋亡来确定清除情况。虽然两个部位的总体初始DNA损伤相似，但在远端结肠中，修复蛋白的表达更高（P < 0.001），靶向凋亡程度也更高（P < 0.0001）。食用鱼油的大鼠远端结肠中的DNA损伤也有所减少。综合这些结果表明，与近端结肠相比，远端结肠肿瘤发生率较低可能是其处理初始DNA损伤能力的结果。因此，确定肿瘤发生的部位特异性机制很重要，因为可能需要不同的策略来预防不同部位的癌症。
