Lack of Expression of the EP2 but not EP3 Receptor for Prostaglandin E2 Results in Suppression of Skin Tumor Development

Abstract

The EP2 receptor for prostaglandin E2 (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. Unlike EP3 knockout mice, the EP2 knockout mice produced significantly fewer tumors and reduced tumor incidence compared with wild type (WT) mice in a 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage carcinogenesis protocol. EP2 knockout mice had significantly reduced cellular proliferation of mouse skin keratinocytes in vivo and in vitro compared with that in WT mice. In addition, the epidermis of EP2 knockout mice 48 hours after topical TPA treatment was significantly thinner compared with that of WT mice. The inflammatory response to TPA was reduced in EP2 knockout mice, based on a reduced number of macrophages in the dermis and a reduced level of interleukin-1α mRNA expression, compared with WT mice. EP2 knockout mice also had significantly reduced epidermal cyclic AMP levels after PGE2 treatment compared with WT mice. Tumors from WT mice produced more blood vessels and fewer apoptotic cells than those of EP2 knockout mice as determined by immunohistochemical staining. Our data suggest that the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in skin tumor development.