Role of Cyclooxygenase-2 on development and progression of colorectal cancer and its chemopreventive effect.

尽管越来越多的研究表明环氧合酶-2（cyclooxygenase-2，考克斯-2）在结直肠肿瘤的发生、发展中起重要作用，但考克斯-2促进结直肠肿瘤发生的机制尚不清楚。一个有趣的发现是考克斯-2的表达削弱了凋亡反应。在本研究中，我们调查了考克斯-2蛋白在结直肠肿瘤中何时开始过表达，以及考克斯-2表达是否与人散发性结直肠癌的增殖和/或凋亡相关。材料与方法：对早期结直肠肿瘤患者进行回顾性分析。使用考克斯-2抗体对石蜡包埋的组织样品进行免疫组织化学分析。连续切片采用Ki-67抗体、TUNEL法及p53免疫组化法检测细胞增殖和凋亡。计算考克斯-2评分、Ki-67标记指数、凋亡指数和p53阳性率 ...更多信息 在肿瘤的表面和更深的部分。分析肿瘤各部位Ki-67标记指数或凋亡指数、p53阳性率与考克斯-2评分的关系。研究结果：在结直肠肿瘤中，免疫反应性考克斯-2的显著表达不仅存在于间质细胞，包括炎性单核细胞、血管内皮细胞和成纤维细胞，而且存在于肿瘤细胞中。考克斯-2阳性率随肿瘤体积增大而增加。癌组织深部考克斯-2评分和p53阳性率均高于癌组织表面。Ki-67标记指数在深部明显低于表层。p53阳性组的考克斯-2评分高于p53阴性组。凋亡指数与考克斯-2评分无相关性。在更深的部分，另一方面，较低的凋亡指数与较高的考克斯-2评分相关。Ki-67标记指数和p53阳性率与考克斯-2评分无相关性。p53阳性组的细胞凋亡指数在浅表和深部均显著低于p53阴性组。结论：这些证据支持了考克斯-2促进结直肠肿瘤发生发展的假说，其机制之一是通过p53非依赖性途径阻止细胞凋亡。少

Although accumulated knowledge has shown that cyclooxygenase-2(COX-2) plays an important role in the occurrence and the progression of colorectal tumor, the mechanism how COX-2 promotes colorectal tumorigenesis remains unclear. One intriguing finding is that the expression of COX-2 impairs the apoptotic response. In this study we investigated when COX-2 protein starts to overexpress in colorectal tumors in the process of developing cancer from adenoma and whether COX-2 expression correlates with proliferation and/or apoptosis in human sporadic colorectal cancers. MATERIALS & METHODS : A retrospective review of patients with early colorectal tumor was performed. Immunohistochemical analysis was performed on paraffin-embedded tissue samples using a COX-2 antibody. Proliferation and apoptosis were investigated on serial sections by Ki-67 antibody and TUNEL method as well as p53 immunohistochemistry. COX-2 score, Ki-67 labeling index, apoptotic index and p53-positive ratio were calculated … More at both surface and deeper parts of the tumor. The relationship between Ki-67 labeling index or apoptotic index, p53-positive ratio and COX-2 score at each part of the tumor was analyzed. RESULTS : In colorectal tumors, marked expression of immunoreactive COX-2 was present not only in interstitial cells including inflammatory mononuclear cells, vascular endothelial cells and fibroblasts, but also in tumor cells. In proportion as the tumor increased in size, COX-2 positive ratio increased. The COX-2 score and p53 positive ratio at deeper part of cancers were higher than those at surface part. Ki-67 labeling index at deeper part was significantly lower than that at surface part. At surface part the COX-2 score of p53-positive cancers was higher than that of p53-negative cancers. The apoptotic index showed no correlation with COX-2 score. At deeper part, on the other hand, lower apoptotic index correlated with higher COX-2 score. The Ki-67 labeling index and p53 positive ratio showed no correlation with COX-2 score. The apoptotic index of p53-positive cancers was significantly lower than that of p53-negative cancers at both surface and deeper parts. CONCLUSIONS : These evidences support the hypothesis that COX-2 promotes development of colorectal tumors, one of which mechanisms is to prevent apoptosis with p53-independent pathway. Less