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

人类流行病学研究表明，结肠癌和其他癌症的发病率显著下降，这与使用非甾体类抗炎药（NSAID）有关。我们已经证明，考克斯-1和考克斯-2的缺陷减少皮肤肿瘤的发生，并认为这种减少是由于改变分化。通过DMBA/TPA处理的小鼠表皮中角蛋白的IHC，我们已经证明了野生型和考克斯缺失小鼠之间角质形成细胞分化的差异。考克斯缺陷型小鼠的基底角质形成细胞过早地开始终末分化，因为与野生型小鼠相比，在考克斯缺陷型小鼠中，K1和K10在这些细胞的高百分比中表达。这种过早的终末分化将不断地从复制群体中去除起始细胞，并降低肿瘤生长和数量。令人惊讶的是，与野生型小鼠中观察到的水平相比，考克斯缺陷小鼠的角质形成细胞的凋亡没有显著增加。因此，这些数据表明，角质形成细胞的终末分化改变可能是一种考克斯依赖性机制，NSAID通过该机制减少皮肤肿瘤发生。

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.