Prostaglandin E receptor EP3 deficiency modifies tumor outcome in mouse two-stage skin carcinogenesis

• Published in: Carcinogenesis (New York) 2005-12, Vol.26 (12), p.2116-2122
• Main Authors: Shoji, Yutaka, Takahashi, Mami, Takasuka, Nobuo, Niho, Naoko, Kitamura, Tomohiro, Sato, Hidetaka, Maruyama, Takayuki, Sugimoto, Yukihiko, Narumiya, Shuh, Sugimura, Takashi, Wakabayashi, Keiji
• Format: Article
• Language: English
• Subjects: 12-dimethylbenz[a]anthracene; 12-O-tetradecanoylphorbol-13-acetate; 9,10-Dimethyl-1,2-benzanthracene - toxicity; aberrant crypt foci; ACF; Animals; AOM; azoxymethane; Biological and medical sciences; Cadherins - metabolism; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; COX; cyclooxygenase; DMBA; Female; Incidence; Keratoacanthoma - chemically induced; Keratoacanthoma - metabolism; Keratoacanthoma - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; PGE2; prostaglandin E2; Receptors, Prostaglandin E - genetics; Receptors, Prostaglandin E - physiology; Receptors, Prostaglandin E, EP3 Subtype; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; SCC; Skin Neoplasms - chemically induced; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; squamous cell carcinoma; Tetradecanoylphorbol Acetate - toxicity; TPA; Treatment Outcome; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi193

We have recently shown that the prostaglandin E2 (PGE2) receptor EP3 plays an important role in suppression of colon cancer cell proliferation and that its deficiency enhances late stage colon carcinogenesis. Here we examined the effects of EP3-deficiency on two-stage skin carcinogenesis. 7,12-Dimethylbenz[a]anthracene (50 µg/200 µl of acetone) was thus applied to the back skin of female EP3-knockout and wild-type mice at 8 weeks of age, followed by treatment with 12-O-tetradecanoylphorbol-13-acetate (5 µg/200 µl of acetone) twice a week for 25 weeks. First tumor appearance was observed in EP3-knockout mice at week 10, which was 3 weeks later than in EP3 wild-type mice, and multiplicity observed at week 11 was significantly lower in the EP3-knockout case. However, histological examination showed that the tumor incidence and multiplicity at week 25 were not significantly changed in knockout mice and wild-type mice (incidence, 19/19 versus 23/24; multiplicity, 3.58 ± 0.51 versus 3.17 ± 0.63, respectively). Interestingly, there were no squamous cell carcinomas (SCCs) in the EP3-knockout mice, while SCCs were observed in 3 out of 24 wild-type mice. Furthermore, benign keratoacanthomas only developed in EP3-knockout mice (6/19 versus 0/24, P < 0.01). The results suggest that PGE2 receptor EP3 signaling might contribute to development of SCCs in the skin.