The tumor promoting activity of the EP4 receptor for prostaglandin E2 in murine skin

• Published in: Molecular oncology 2014-12, Vol.8 (8), p.1626-1639
• Main Authors: Simper, Melissa S., Rundhaug, Joyce E., Mikulec, Carol, Bowen, Rebecca, Shen, Jianjun, Lu, Yue, Lin, Kevin, Surh, Inok, Fischer, Susan M.
• Format: Article
• Language: English
• Subjects: Animals; Anthracene; Carcinogenesis; Cell adhesion & migration; Cytotoxicity; EP4 receptor; Epidermis; Inflammation; Interleukins - metabolism; Kinases; Metabolism; Metabolites; Mice; Mice, Transgenic; Murine skin; Prostaglandin E; Prostaglandin E2; Proteins; Receptors, Prostaglandin E, EP4 Subtype - genetics; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Signal transduction; Skin; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin tumors; Squamous cell carcinoma; Transgenic animals; Tumor promotion; Ultraviolet radiation; Wound healing; Wound Healing - physiology
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2014.06.013

To determine whether the EP4 receptor for prostaglandin E2 (PGE2) contributes to the tumor promoting activity of PGs in murine skin, EP4 over-expressing mice (BK5.EP4) were generated and subjected carcinogenesis protocols. An initiation/promotion protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. An increase in SCCs also occurred following treatment with initiator alone or UV irradiation. The initiator dimethylbenz[a]anthracene caused cytotoxicity in BK5.EP4, but not WT mice, characterized by sloughing of the interfollicular epidermis, regeneration and subsequent SCC development. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, supporting a pro-tumorigenic role for the EP4 receptor. •Transgenic mice overexpressing the EP4 receptor for prostaglandin E2 (PGE2) were generated.•The EP4 transgene conferred endogenous tumor promoting and progression activity in skin.•The transcriptomes of BK5.EP4 and wild type mice treated with PGE2 were compared.•Genes associated with tumor development were upregulated in BK5.EP4 mice.•Interleukin-20 was among the most highly upregulated in BK5.EP4 mice.