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

环加氧酶-1 和-2 在紫外线诱导的皮肤癌中的作用

• 批准号: 7593870
• 负责人: Robert Langenbach
• 金额: $ 24.41万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593870
• 关键词: Acute; Alleles; Apoptosis; Apoptotic; Causations; Cells; Chemicals; Chronic; Cutaneous; Data; Development; Dinoprostone; Enzymes; Genotype; Goals; Immunohistochemistry; Individual; Measures; Mouse Strains; Mus; Numbers; Outcome; PTGS2 gene; Play; Production; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Research; Role; Skin; Skin Cancer; Skin Neoplasms; Source; Sunburn; Thick; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Wild Type Mouse; carcinogenesis; cyclooxygenase 1; cyclooxygenase 2; environmental agent; epidemiology study; research study; response; size; tumor; ultraviolet

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.

流行病学研究表明，紫外线（UV）辐射造成皮肤损伤，是导致皮肤癌的主要环境因素。虽然已经确定组成型和诱导型环氧合酶（分别为考克斯-1和考克斯-2）在化学诱导的皮肤肿瘤中起重要作用，但这两种酶对UV光诱导的皮肤肿瘤的贡献尚未得到充分评估。 环氧合酶考克斯-1和考克斯-2参与皮肤对急性和慢性紫外线暴露的反应。在目前的研究中，野生型（WT），考克斯-1-/-和考克斯-2-/-小鼠用于确定的影响，个别亚型对小鼠皮肤的反应，急性UVB治疗。免疫组化和Western分析表明，考克斯-2，而不是考克斯-1，诱导UVB（2.5或5.0 kJ/m2），但考克斯-1仍然是前列腺素E2生产的主要来源。UVB暴露显着增加表皮细胞凋亡在所有基因型相比，未经处理的小鼠。然而，虽然WT和考克斯-1-/-小鼠中的凋亡细胞数量大致相等，但考克斯-2-/-小鼠中的凋亡细胞数量是其2.5倍。WT和考克斯-2-/-小鼠的细胞凋亡在暴露后24 h达到峰值。考克斯-2-/-小鼠中细胞凋亡增加和增殖减少导致暴露后24 - 48 h表皮厚度减少约50%，而WT小鼠中表皮厚度增加约50%。 为了更好地理解考克斯-1和考克斯-2对紫外线致癌作用的贡献，我们将每个同种型的无效等位基因转移到SKH-1无毛小鼠品系中。由于考克斯-2在SKH-1小鼠上的低存活率，在UV诱导的致癌实验中使用杂合小鼠。虽然考克斯-1的一个等位基因的缺失对肿瘤结果没有影响，但是考克斯-2的一个等位基因的缺失导致肿瘤多样性减少50 - 65%，并且肿瘤大小显著减小。 考克斯-1或考克斯-2的一个等位基因的缺失降低了响应于单一UV处理的前列腺素（PG）E2水平。在考克斯-2，但不是考克斯-1，杂合子小鼠的增殖反应，紫外线显着减少。然而，在考克斯-2杂合子小鼠中，UV诱导的细胞凋亡更大。总的来说，这些结果清楚地确立了皮肤肿瘤发展中对考克斯-2的需求。 总体而言，数据表明，考克斯-2诱导最初保护免受UVB的急性晒伤效应，但持续诱导考克斯-2可能有助于皮肤癌在慢性UVB暴露。