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. ? ?
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