Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression
Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression
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DOI：
10.1093/carcin/bgq002
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发表时间：
2010-04-01
期刊：
影响因子：
4.7
通讯作者：
Herschman, Harvey R.
中科院分区：
文献类型：
--
作者：
Ishikawa, Tomo-o;Herschman, Harvey R.
环氧合酶-2（Cyclooxygenase-2，考克斯-2）是前列腺素生物合成的关键酶，在遗传性和自发性结肠癌中均起重要作用。患有溃疡性结肠炎的人也有患结肠直肠癌的高风险。为了研究考克斯-2在结肠炎相关结肠癌中的作用，我们将考克斯-2辅酶敲入小鼠和考克斯-2敲除小鼠置于众所周知的结肠炎相关癌症小鼠模型中，在该模型中，动物用单次氧化偶氮甲烷（AOM）注射治疗，然后给予葡聚糖硫酸钠（DSS）。通过内源性考克斯-2启动子驱动的荧光素酶报告基因表达和考克斯-2荧光素酶杂合敲入小鼠中考克斯-2蛋白的蛋白质印迹检测，与结肠周围区域相比，AOM和DSS诱导的肿瘤表达显著更高的考克斯-2水平。免疫荧光显示肿瘤间质成纤维细胞、巨噬细胞和内皮细胞表达考克斯-2蛋白。相反，在肌成纤维细胞或上皮细胞中观察到很少的考克斯-2表达。尽管AOM/DSS诱导的野生型小鼠结肠肿瘤中考克斯-2表达显著升高，但AOM/DSS处理的考克斯-2（-/-）-和考克斯-1（-/-）-敲除小鼠中也发生了类似的肿瘤。这些结果表明，环氧化酶衍生的前列腺素类不是结肠炎相关癌症的主要参与者。相反，在考克斯-2（-/-）基因敲除小鼠中，多次注射AOM诱导的肿瘤形成（无DSS诱导的结肠炎）未发生。我们的数据表明，结肠炎相关性癌症的结直肠肿瘤促进机制不同于遗传性和散发性结直肠癌的肿瘤促进机制。
Cyclooxygenase-2 (COX-2), a key enzyme of prostanoid biosynthesis, plays an important role in both hereditary and spontaneous colon cancer. Individuals with ulcerative colitis are also at high risk for colorectal cancer. To investigate the role of Cox-2 in colitis-associated colon cancer, we subjected Cox-2 luciferase-knock-in mice and Cox-2-knockout mice to a well-known mouse model of colitis-associated cancer in which animals are treated with a single-azoxymethane (AOM) injection followed by dextran sulfate sodium (DSS) administration. Tumors induced by AOM and DSS expressed significantly higher Cox-2 levels when compared with surrounding areas of colon, as detected both by luciferase reporter gene expression driven from the endogenous Cox-2 promoter and by western blotting of COX-2 protein in Cox-2 luciferase heterozygous knock-in mice. Immunofluorescence revealed that tumor stromal fibroblasts, macrophages and endothelial cells express COX-2 protein. In contrast, little COX-2 expression was observed in myofibroblasts or epithelial cells. Despite a significant elevation of COX-2 expression in AOM/DSS-induced colon tumors in wild-type mice, similar tumors developed in AOM/DSS-treated Cox-2(-/-)- and Cox-1(-/-)-knockout mice. These results indicate that cyclooxygenase-derived prostanoids are not major players in colitis-associated cancer. In contrast, tumor formation induced by multiple injections of AOM (with no DSS-induced colitis) did not occur in Cox-2(-/-)-knockout mice. Our data suggest that the mechanism of colorectal tumor promotion in colitis-associated cancer differs from the mechanism of tumor promotion for hereditary and sporadic colorectal cancer.