Effect of COX-1 or COX-2 Deficiency on Epidermal Differe

在人类中的流行病学研究表明，与使用非类固醇抗炎药(NSAIDs)相关的结肠癌和其他癌症的发病率显著下降。我们已经证明COX-1和COX-2的缺失可以减少皮肤肿瘤的发生，并相信这种减少是由于分化改变所致。通过对DMBA/TPA处理的小鼠表皮角质形成蛋白的免疫组化检测，我们证实了野生型和COX缺失型小鼠角质形成细胞分化的差异。COX基因缺陷小鼠的基底角质形成细胞提前开始终末分化，因为与野生型小鼠相比，COX基因缺陷小鼠的角质形成细胞中K1和K10的表达比例较高。这种终末分化的过早开始会不断地从复制群体中移除启动的细胞，并减少肿瘤的生长和数量。令人惊讶的是，与野生型小鼠相比，COX缺陷小鼠角质形成细胞的凋亡率并没有显著增加。因此，这些数据表明角质形成细胞终末分化的改变可能是非类固醇类抗炎药降低皮肤肿瘤发生的COX依赖机制。

Epidemiological studies in humans have shown a marked decrease in colon and other cancers that correlates with the use of nonsteroidal antiinflammatory drugs (NSAIDs). We have demonstrated that COX-1 and COX-2 deficiencies reduce skin tumorigenesis and believe this reduction is due to altered differentiation. By IHC of keratins in the epidermis of DMBA/TPA treated mice, we have demonstrated differences in keratinocyte differentiation between the wild type and COX null mice. The basal keratinocytes of COX deficient mice began terminal differentiation prematurely, as K1 and K10 are expressed in a high percentage of these cell in the COX deficient mice compared to wild type mice. This premature onset of terminal differentiation would continually remove initiated cell from the replicative population and decrease tumor growth and numbers. Surprisingly, apoptosis of keratinocytes of the COX deficient mice was not significantly increased compared to the level observed in wild type mice. Thus, the data suggest that altered terminal differentiation of keratinocytes may be a COX dependent mechanism by which NSAIDs reduce skin tumorigenesis.