Abstract 1082: IL27 promotes papilloma formation via inducing a pro-inflammatory milieu in the skin

Abstract

Ras activation plays an important role in Squamous Cell Carcinomas (SCC) development. Additionally, there is large evidence confirming the role of inflammation during cancer initiation. However, the interaction between inflammation and oncogene activation is poorly understood in tumorigenesis. We found that IL27 promotes papilloma formation in a 2 step skin carcinogenesis (DMBA followed by benzoyl peroxide) model where DMBA causes Ras mutation. Because K15-positive follicular stem cells contribute to papillomas in the two-step skin carcinogenesis model, we used an inducible oncogenic K-RasG12D under the K15 promoter, which marks follicular stem cells. Indeed, treating mice with IL27 increased papilloma incidence earlier in these K15-K-RASG12D mice. Mechanistically, we see that ETAR+ macrophages are significantly increased in IL27-treated K15-K-RasG12D mice. Additionally, the ETAR ligand ET1, and the downstream factor of ETAR, COX2, are upregulated in these K15-KRasG12D mice by IL27, suggesting that ET1/ETAR pathway is involved in IL27 mediated papilloma formation. Indeed, IL27-mediated papilloma formation was reversed by using the ETAR inhibitor ZD4054. Therefore, the data shown here suggest that IL27 drives accumulation of ETAR+ macrophages, ET1, and Cox-2 in the skin and ultimately causes faster papilloma formation in K-Ras mutated follicular stem cells. These findings propose an unrecognized role of IL27 during initiation of skin carcinogenesis. Citation Format: Denada Dibra, Xueqing Xia, Melissa Newman, Camille Keenan, Shulin Li. IL27 promotes papilloma formation via inducing a pro-inflammatory milieu in the skin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1082. doi:10.1158/1538-7445.AM2014-1082