PGE2 Receptor Function in Skin

紫外线是一种完全的致癌物质，可诱发和促进皮肤鳞状细胞癌（SCC）。我们最近的研究表明，SCC的启动和促进是由前列腺素E2（PGE 2）增强。PGE 2与特定的EP受体相互作用以调节细胞功能。EP受体（1-4）和8种人EP 3同种型介导PGE 2受体信号传导。该实验室的初步数据表明，这些受体可能协调相互作用，以改变PGE 2介导的信号传导，并增强UV肿瘤发生。到目前为止，我们已经表明，1 ½人角质形成细胞表达PGE 2的生长刺激（EP 2）和生长抑制（EP 3）受体。我们的数据表明，EP 3受体信号在低浓度的PGE 2下降低增殖，而10倍高浓度的PGE 2通过EP 2受体活化刺激增殖。每种受体的活性取决于表皮中PGE 2的水平，其可由两种环氧合酶（考克斯）同种型中的任一种合成。这表明通过EP受体的信号传导可能是光致癌作用的重要治疗靶点。我们对EP 2-/-无毛小鼠的数据支持这一模型。我们推测PGE 2信号通过EP受体介导修复UV损伤所需的增生、增殖和分化反应。当EP信号传导不适当协调时，可发生乳头状瘤形成和肿瘤进展。由于EP受体对PGE 2的亲和力变化1000倍，需要同时了解表皮合成前列腺素的能力。拟议的工作将界定：1）急性UV损伤后PGE 2 &EP受体调节如何改变表皮生长和分化，2）在小鼠和人类模型中鉴定辐射对PGE 2 & EP受体调节和功能的慢性影响3）确定SCC患者与无皮肤癌史的对照组相比是否存在改变的PGE 2 & EP受体表达/调节。

DESCRIPTION (provided by applicant): Ultraviolet light is a complete carcinogen, inducing & promoting squamous cell carcinoma (SCC) of the skin. Our recent work has shown that SCC initiation and promotion are enhanced by prostaglandin E2(PGE2). PGE2 interacts with specific EP receptors to regulate cellular functions. EP receptors(1-4) & 8 human EP3 isoforms mediate PGE2 receptor signaling. Initial data from this lab suggests these receptors may interact coordinately to alter PGE2 mediated signaling arid to enhance UV tumorigenesis. To date, we have shown that 1¿ human keratinocytes express both growth-stimulatory (EP2) and growth-inhibitory (EP3) receptors for PGE2. Our data shows that EP3 receptor signaling decreases proliferation at low PGE2 concentrations, while 10-fold higher concentrations of PGE2 stimulate proliferation by EP2 receptor activation. The activity of each receptor depends upon the level of PGE2 in epidermis, which may be synthesized by either of two cyclooxygenase (COX) isoforms. This suggests that signaling via EP receptors may be an important therapeutic target for photocarcinogenesis. Our data with EP2 -/- hairless mice support this model. We hypothesize that PGE2 signaling through EP receptors functions to mediate hyperplastic, proliferative and differentiation responses needed to repair UV injury. When EP signaling is not properly coordinated, papilloma formation and tumor progression can occur. Since EP receptor affinity for PGE2 varies 1000 fold, concurrent understanding of the epidermal capacity to synthesize prostaglandin is needed. The work proposed will define: 1) How PGE2 &EP receptor regulation after acute UV injury modifies epidermal growth and differentiation, 2) Identify chronic effects of irradiation on PGE2 & EP receptor regulation & function in mouse and human models 3) Determine whether altered PGE2 & EP receptor expression/regulation is present in SCC patients vs controls with no history of skin cancer.