PGE2 Receptor Function in Skin

描述（申请人提供）：紫外线是一种完全致癌物质，可诱导和促进皮肤鳞状细胞癌（SCC）。我们最近的工作表明，前列腺素E2（PGE2）可增强SCC的发生和促进。PGE2与特定EP受体相互作用，调节细胞功能。EP受体（1-4）和8种人类EP3亚型介导PGE2受体信号传导。该实验室的初步数据表明，这些受体可能协同作用，改变PGE2介导的信号传导，从而增强紫外线肿瘤的发生。迄今为止，我们已经证明1 / 8人角质形成细胞表达PGE2的生长刺激（EP2）和生长抑制（EP3）受体。我们的数据表明，EP3受体信号在低浓度的PGE2下会抑制增殖，而PGE2浓度高出10倍时，EP2受体的激活会刺激增殖。每种受体的活性取决于表皮中PGE2的水平，PGE2可以由两种环氧化酶（COX）亚型中的任何一种合成。这表明通过EP受体的信号传导可能是光癌发生的重要治疗靶点。我们的EP2 -/-无毛小鼠数据支持这一模型。我们假设PGE2信号通过EP受体介导了修复紫外线损伤所需的增生、增殖和分化反应。当EP信号不能正常协调时，可能发生乳头状瘤的形成和肿瘤的进展。由于EP受体对PGE2的亲和力相差1000倍，因此需要同时了解表皮合成前列腺素的能力。这项工作将定义：1)急性紫外线损伤后PGE2和EP受体的调节如何改变表皮生长和分化；2)在小鼠和人类模型中确定照射对PGE2和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中是否存在PGE2和EP受体表达/调节的改变。

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.