Upregulation of the EP1 receptor for prostaglandin E2 promotes skin tumor progression.
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.
The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Inok
I
Surh
Joyce
J
Rundhaug
Amy
A
Pavone
Carol
C
Mikulec
Erika
E
Abel
Susan M
SM
Fischer
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism*; D018450:Disease Progression; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D005260:Female; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism*; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014466:Ultraviolet Rays; D015854:Up-Regulation
D002273:Carcinogens; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015127:9,10-Dimethyl-1,2-benzanthracene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate