Reduced COX-2 protein in colorectal cancer with defective mismatch repair.
Reduced COX-2 protein in colorectal cancer with defective mismatch repair.
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DOI：
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发表时间：
1998-12
期刊：
影响因子：
11.2
通讯作者：
W. Karnes;R. Shattuck-Brandt;L. Burgart;R. Dubois;D. Tester;J. Cunningham;C. Y. Kim;S. McDonnell-S.-McDonne
中科院分区：
文献类型：
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作者：
W. Karnes;R. Shattuck-Brandt;L. Burgart;R. Dubois;D. Tester;J. Cunningham;C. Y. Kim;S. McDonnell-S.-McDonne
大多数结直肠腺瘤和癌是在染色体不稳定的情况下发生的，其特征是杂合性的逐渐丧失。相比之下，大约15-20%的结直肠肿瘤是通过一种独特的遗传途径发生的，其特征是微卫星不稳定性（MSI），与一种DNA错配修复酶（最常见的是hMLH1或hMSH2）的频繁表达缺失有关。这些不同的遗传途径反映在肿瘤组织病理学、结肠分布、预后和从腺瘤到癌进展所需的停留时间的差异上。为了确定这两组肿瘤在环氧化酶-2 （COX-2）的表达上是否存在差异，在存在（n = 41）和不存在（n = 66）缺陷错配修复的结直肠癌中对该蛋白进行了免疫染色。环氧化酶-2是一种假定的化学预防靶点。缺陷错配修复的定义是肿瘤微卫星不稳定性（MSI-H, >或=40%的标记物显示不稳定性）的存在以及hMLH1或hMSH2蛋白表达的缺失。总的来说，我们的结果显示低水平或缺失COX-2染色在错配修复缺陷的肿瘤中更为常见（P = 0.001）。其他预测低COX-2染色的特征包括明显的肿瘤浸润性淋巴细胞增多，实型/筛状或印戒组织模式。这些观察结果表明，具有缺陷DNA错配修复的分子和表型特征的结直肠癌表达较低水平的COX-2。这种生物学差异的临床意义尚不清楚，但在评估COX-2抑制剂对DNA错配修复缺陷中可能出现肿瘤的患者的化学预防效果时应考虑到这一点。
Most colorectal adenomas and carcinomas arise in the setting of chromosomal instability characterized by progressive loss of heterozygosity. In contrast, approximately 15-20% of colorectal neoplasms arise through a distinct genetic pathway characterized by microsatellite instability (MSI) associated with frequent loss of expression of one of the DNA mismatch repair enzymes, most often hMLH1 or hMSH2. These distinct genetic pathways are reflected by differences in tumor histopathology, distribution in the colon, prognosis, and dwell time required for progression from adenoma to carcinoma. To determine whether these two groups of tumors differ in their expression of cyclooxygenase-2 (COX-2), a putative chemopreventative target, immunostaining for this protein was performed in colorectal cancers categorized by the presence (n = 41) and absence (n = 66) of defective mismatch repair. Defective mismatch repair was defined by the presence of tumor microsatellite instability (MSI-H, > or =40% of markers demonstrating instability) and by the absence of protein expression for either hMLH1 or hMSH2. Overall, our results showed that low or absent COX-2 staining was significantly more common among tumors with defective mismatch repair (P = 0.001). Other features predictive of low COX-2 staining included marked tumor infiltrating lymphocytosis, and solid/cribiform or signet ring histological patterns. These observations indicate that colorectal cancers with molecular and phenotypic characteristics of defective DNA mismatch repair express lower levels of COX-2. The clinical implications of this biological distinction remain unknown but should be considered when assessing the efficacy of COX-2 inhibitors for chemoprevention in patients whose tumors may arise in the setting of defective DNA mismatch repair.