The role of EP1 receptor for prostaglandin E₂ in mouse skin carcinogenesis



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Prostaglandin E₂ (PGE₂), the most abundant prostaglandin in mouse skin, has been shown to promote skin tumor development. EP1 is one of four PGE₂ receptors. EP1 mRNA levels analyzed by a quantitative real-time polymerase chain reaction were increased after treatments of 12-O-tetradecanoylphorbol 13-acetate (TPA) or ultraviolet light on skin as well as in 7,12 dimethylbenz[a]anthracene (DMBA)/TPA or UV-induced skin tumors. To determine whether the EP1 receptor levels affect skin tumor development, we generated BK5.EP1 transgenic mice which overexpress EP1 in the basal layer of the epidermis. The skins of these mice are histologically indistinguishable from wild type mice. To determine the role of EP1 in skin tumor development, a DMBA/TPA skin carcinogenesis protocol was used. EP1 transgenic mice had a reduced tumor multiplicity and a reduced tumor incidence compared to wild type mice, but had a higher papilloma to carcinoma conversion rate. In a DMBA-only skin carcinogenesis protocol, EP1 transgenic mice developed more tumors than wild type mice. The effect of EP1 on cell proliferation was measured in vivo. After TPA treatment, cell proliferation was induced in both EP1 transgenic mice and wild type mice to a similar extent. However, 5 days after DMBA treatment, there were about 2-fold more proliferating cells in the basal layer of the epidermis of EP1 transgenic mouse skin than in wild type mice. To confirm that the enhanced tumor formation in transgenic mice is in fact PGE₂ dependent, EP1 transgenic mice were administered the selective cyclooxygenase-2 inhibitor Celecoxib or a control diet starting 1 week before DMBA treatment. Surprisingly, there was no lesion development on mice that were fed Celecoxib. Histological sections of skin from Celecoxib-fed mice showed a fairly normal skin histology 2 weeks after DMBA treatment compared to the pronounced pseudocarcinomatous hyperplasia observed in control diet mice. Therefore, it can be concluded that EP1 signaling increases PGE₂ production through COX-2 induction and promotes tumor development.