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Upregulation of the EP1 receptor for prostaglandin E 2 promotes skin tumor progression
Author(s) -
Surh Inok,
Rundhaug Joyce,
Pavone Amy,
Mikulec Carol,
Abel Erika,
Fischer Susan M.
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20730
Subject(s) - dmba , biology , prostaglandin e , genetically modified mouse , tumor promotion , prostaglandin e2 , 12 o tetradecanoylphorbol 13 acetate , receptor , prostaglandin , tetradecanoylphorbol acetate , endocrinology , cancer research , microbiology and biotechnology , carcinogenesis , medicine , transgene , kinase , protein kinase c , biochemistry , phorbol ester , gene
Abstract Prostaglandin E 2 (PGE 2 ) has been shown to promote the development of murine skin tumors. EP1 is 1 of the 4 PGE 2 G‐protein‐coupled membrane receptors expressed by murine keratinocytes. EP1 mRNA levels were increased ∼2‐fold after topical treatment with 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) or exposure to ultraviolet (UV) light, as well as increased ∼3‐ to 12‐fold in tumors induced by 7,12‐dimethyl‐benz[ a ]anthracene (DMBA) initiation/TPA promotion or by UV exposure. To determine the effect of EP1 levels on tumor development, we generated BK5.EP1 transgenic mice that overexpress EP1 in the basal layer of the epidermis. Skins of these mice were histologically indistinguishable from wild type (WT) mice and had similar levels of proliferation after TPA treatment. Using a DMBA/TPA carcinogenesis protocol, BK5.EP1 mice had a reduced tumor multiplicity compared to WT mice, likely due to the observed down‐regulation of protein kinase C (PKC). However, the BK5.EP1 mice had an ∼8‐fold higher papilloma to carcinoma conversion rate. When DMBA/anthralin was used, BK5.EP1 mice produced more tumors than WT mice, as well as a ninefold increase in carcinomas, indicating that the tumor response is dependent on the type of tumor promoter agent used. Additionally, although almost undetectable in WT mice, cyclooxygenase‐2 (COX‐2) was expressed in the untreated epidermis of BK5.EP1 mice. While TPA highly induced COX‐2 in WT mice, COX‐2 expression in the BK5.EP1 mice did not change after TPA treatment; PGE 2 levels were likewise affected. These data indicate that EP1 is more important in tumor progression than in tumor promotion and that it indirectly regulates COX‐2 expression. © 2011 Wiley‐Liss, Inc.