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: 7734410
• 负责人: Robert Langenbach
• 金额: $ 23.4万
• 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/7734410
• 关键词: Acute; Affect; Apoptotic; Causations; Cell Survival; Cells; Chemicals; Chronic; Cutaneous; Data; Development; Enzymes; Epidermal Growth Factor Receptor; Epidermis; Genotype; Goals; Immunohistochemistry; Individual; Indomethacin; Measures; Mediator of activation protein; Mus; Numbers; PTGS2 gene; Play; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Research; Role; Skin; Skin Cancer; Skin Neoplasms; Source; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Wild Type Mouse; cell injury; cyclooxygenase 1; cyclooxygenase 2; environmental agent; epidemiology study; response; survivin; transcription factor; 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 skin damage and tumor development is poorly understood. The cyclooxygenases, COX-1 and COX-2, are involved in cutaneous responses to both acute and chronic UV exposure. In previous 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, but COX-1 remained the major source of prostaglandin (PG) production. UVB exposure significantly increased epidermal damage in all genotypes compared to untreated mice, however, the extent of epidermal damage and number of apoptotic cells was significantly greater in COX-2-/- mice. To better understand the contribution of COX-1 and COX-2 to UV effects on skin, we investigated the effects of COX deficiency on the expression of epidermal cell survival effectors following acute UVB exposure. It was observed that induction of the transcription factor p-STAT was significantly reduced in the epidermis of COX-2-/- mice compared to WT mice following UVB exposure. Furthermore survivin levels were also significantly reduced in the COX-2-/- epidermis compared to WT mice. To show that these effects were dependent on reduced PG production in COX-2-/- mice, Indomethacin treatment of WT mice also reduced p-STAT and survivin levels following UVB exposure. In addition to reduced p-STAT and survivin in UV exposed COX-2-/- mice, the levels of p-ERK1/2, EGFR and Ras were also observed to be reduced in the epidermis of UV exposed COX-2-/- mice. Overall, the data indicate that COX-2 protects against the acute UVB-induced skin damage affects, but that continuous induction of COX-2 and PG levels 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。虽然已经确定环氧合酶的组成型和诱导型（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光诱导的皮肤损伤和肿瘤发展的贡献知之甚少。 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。在以前的研究中，野生型（WT），考克斯-1-/-和考克斯-2-/-小鼠被用来确定的影响，个别亚型对小鼠皮肤反应急性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，但考克斯-1仍然是前列腺素（PG）的生产的主要来源。与未处理的小鼠相比，UVB暴露显著增加了所有基因型的表皮损伤，然而，考克斯-2-/-小鼠的表皮损伤程度和凋亡细胞数量显著更大。 为了更好地了解考克斯-1和考克斯-2的紫外线对皮肤的影响的贡献，我们调查了考克斯缺陷的影响表皮细胞生存效应表达急性UVB暴露。据观察，在UVB暴露后，与WT小鼠相比，考克斯-2-/-小鼠表皮中转录因子p-STAT的诱导显著降低。此外，与WT小鼠相比，考克斯-2-/-表皮中的生存素水平也显着降低。为了表明这些作用依赖于考克斯-2-/-小鼠中PG产生的减少，WT小鼠的吲哚美辛治疗也降低了UVB暴露后的p-STAT和存活素水平。除了暴露于紫外线的考克斯-2-/-小鼠中p-STAT和生存素减少外，还观察到暴露于紫外线的考克斯-2-/-小鼠表皮中p-ERK 1/2、EGFR和Ras的水平减少。 总体而言，数据表明，考克斯-2保护免受急性UVB诱导的皮肤损伤影响，但持续诱导考克斯-2和PG水平可能有助于皮肤癌在慢性UVB暴露。