The role of the EP2 receptor for prostaglandin E2 in mouse skin carcinogenesis
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Prostaglandin E2 (PGE2) is the major prostaglandin produced by COX enzymes in the skin and is reported to increase cAMP levels in human and rodent skin. The EP2 receptor for PGE2 is a membrane receptor that mediates at least part of the action of PGE2. It has been shown that EP2 plays a critical role in tumorigenesis in mouse mammary gland and colon. However, the possibility that the EP2 receptor is involved in the development of skin tumors was unknown. The purpose of this study was to investigate the role of the EP2 receptor in mouse skin carcinogenesis. In the first study, we showed that deletion of expression of the EP2, but not the EP3 receptor, for PGE2 results in suppression of skin tumor development in a DMBA (7,12- dimethylbenz[a]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis protocol and is associated with decreased proliferation, angiogenesis, viii inflammation and cell survival. In the second study, to determine the effect of overexpression of EP2, we used EP2 transgenic and wild type mice in a DMBA/TPA two-stage carcinogenesis protocol. We have shown that the overexpression of the EP2 receptor for PGE2 results in enhancement of skin tumor development and is associated with increased proliferation, angiogenesis and inflammation. Based on the first and second studies, further studies are needed to elucidate the underlying molecular mechanisms. Therefore, in the third study, we found EP2 mediated protein kinase A (PKA)/CREB signaling pathway is a central mechanism for inducing a positive feedback loop and further to induce PGE2 effects on cell proliferation and angiogenesis of mouse skin. Collectively, these findings suggest that the EP2 receptor plays a significant role in the pro-tumorigenic action of PGE2 in skin tumor development.