Roles Of Cyclooxygenase-1 and -2 In UV-induced Skin Cancer

流行病学研究表明，紫外线(UV)辐射会导致皮肤损伤，是导致皮肤癌的主要环境因素。虽然环氧合酶的组成形式和诱导形式(分别为COX-1和COX-2)在化学诱导的皮肤肿瘤中都起着重要的作用，但这两种酶在紫外线诱导的皮肤肿瘤中的作用还没有得到充分的评估。 环氧合酶COX-1和COX-2参与皮肤对急性和慢性紫外线暴露的反应。在本研究中，使用野生型(WT)、COX-1-/-和COX-2-/-小鼠来确定个体亚型对急性UVB治疗小鼠皮肤反应的影响。免疫组织化学和Western分析表明，UVB(2.5或5.0kJ/m2)可诱导COX-2而不是COX-1，但COX-1仍是前列腺素E_2产生的主要来源。与未经治疗的小鼠相比，UVB暴露显著增加了所有基因型小鼠的表皮细胞凋亡率。然而，尽管WT和COX-1-/-小鼠的凋亡细胞数量大致相同，但COX-2-/-小鼠的凋亡细胞数量是WT-2-/-小鼠的2.5倍。WT和COX-2-/-小鼠的细胞凋亡在暴露后24小时达到高峰。在暴露后24-48小时，COX-2-/-小鼠的细胞凋亡增加和增殖减少导致表皮厚度减少了约50%，而WT小鼠的表皮厚度增加了约50%。 为了更好地了解COX-1和COX-2在紫外线致癌中的作用，我们将每个亚型的零等位基因转移到SKH-1无毛小鼠品系中。由于COX-2在SKH-1小鼠体内的存活率较低，因此采用杂合子小鼠进行紫外线致癌实验。虽然COX-1缺乏一个等位基因对肿瘤预后没有影响，但COX-2缺乏一个等位基因会导致肿瘤多样性减少50%-65%，肿瘤大小显著缩小。缺乏COX-1或COX-2的一个等位基因会降低前列腺素(PG)E2水平，以应对单一的紫外线治疗。COX-2杂合子小鼠对紫外线的增殖反应显著降低，但COX-1杂合子小鼠对紫外线的增殖反应不明显。然而，紫外线诱导的细胞凋亡在COX-2杂合子小鼠中更大。总而言之，这些结果清楚地确立了在皮肤肿瘤的发展中对COX-2的要求。 总体而言，数据表明，COX-2的诱导最初对UVB的急性晒伤效应具有保护作用，但持续诱导COX-2可能导致慢性UVB暴露中的皮肤癌。

Epidemiology studies indicate that ultraviolet (UV) radiation causes skin damage and is a major environmental agent in the causation of skin cancer. While it has been established that both the constitutive and inducible forms of cyclooxygenase (COX-1 and COX-2, respectively) play important roles in chemical induced skin tumors, the contribution of these two enzymes to UV light-induced skin tumors has not been fully assessed. The cyclooxygenases, COX-1 and COX-2, are involved in cutaneous responses to both acute and chronic UV exposure. In the present studies, wild-type (WT), COX-1-/- and COX-2-/- mice were used to determine the influence of the individual isoform on mouse skin responses to acute UVB treatment. Immunohistochemistry and Western analysis indicated that COX-2, and not COX-1, was induced by UVB (2.5 or 5.0 kJ/m2), but that COX-1 remained the major source of prostaglandin E2 production. UVB exposure significantly increased epidermal apoptosis in all genotypes compared to untreated mice. However, while the number of apoptotic cells in WT and COX-1-/- mice were about equal, the number of apoptotic cells was 2.5-fold greater in COX-2-/- mice. Apoptosis in WT and COX-2-/- mice peaked at 24 h post-exposure. The increased apoptosis and reduced proliferation in COX-2-/- mice resulted in about a 50% decrease in epidermal thickness at 24-48 h post-exposure compared to about a 50% increase in epidermal thickness in WT mice. To better understand the contribution of COX-1 and COX-2 to UV carcinogenesis, we transferred the null allele for each isoform onto the SKH-1 hairless strain of mouse. Due to low viability of COX-2 on SKH-1 mice, heterozygous mice were used in the UV induced carcinogenesis experiments. While the lack of one allele of COX-1 had no effect on tumor outcome, the lack of one allele of COX-2 resulted in a 50-65% reduction in tumor multiplicity and a marked decrease in tumor size. The lack of one allele of either COX-1 or COX-2 reduced prostaglandin (PG) E2 levels in response to a single UV treatment. The proliferative response to UV was significantly reduced in COX-2, but not COX-1, heterozygous mice. UV-induced apoptosis, however, was greater in COX-2 heterozygous mice. Collectively, these results clearly establish the requirement for COX-2 in the development of skin tumors. Overall, the data indicate that COX-2 induction initially protects against the acute sunburn effects of UVB, but that continuous induction of COX-2 may contribute to skin cancer in chronic UVB exposure.