Abstract 2480: Role of Stat1 in epithelial carcinogenesis

Abstract

Abstract Aberrant expression and/ or activity of STATs 1, 3, and 5 have been reported in multiple human cancers as well as in murine models of tumorigenesis. Previous work performed in our lab demonstrated a critical role for Stat3 in mediating the initiation and promotion stages of epithelial multi-stage carcinogenesis in mouse skin. In light of these findings, we have begun investigating the role of other STATs, particularly Stat1, in multistage skin carcinogenesis using both wild-type and Stat1 knockout (KO) mice. Western blot analyses revealed that topical application of the skin tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) and chrysarobin induced phosphorylation of Stat1 in mouse epidermis. In addition, following treatment with chrysarobin, the level of total Stat1 protein was also dramatically elevated. To further investigate the role of Stat1 during epithelial carcinogenesis, Stat1 KO mice and wild-type littermates were initiated with 25 nmol DMBA and promoted with either 6.8 nmol TPA or 220 nmol chrysarobin. No significant differences were observed in either tumor incidence or multiplicity when TPA was used as the promoting agent, suggesting that Stat1 does not play a significant role in TPA-mediated skin tumor promotion. In contrast, Stat1 KO mice exhibited a dramatic reduction in both tumor multiplicity and incidence as compared to wild-type littermates when chrysarobin was used as the promoting agent. Additionally, following topical treatment with chrysarobin, Stat1 KO mice had a reduced epidermal proliferative response. To further investigate the impact of Stat1 deletion on chrysarobin-induced tumor promotion, Stat1 KO mice and wild-type controls were treated topically with chrysarobin and the inflammatory response was assessed. Stat1 KO mice displayed a significant reduction in Cox-2 induction compared to wild-type controls. Preliminary findings also showed that Stat1 KO mice have reduced immune cell influx following chrysarobin treatment. To investigate the potential role of reactive oxygen species (ROS) in the effects of chrysarobin on Stat1 activation, the dorsal skin of FVB mice were pre-treated topically with the anti-oxidants ascorbyl palmitate and α-tocopherol acetate. Topical application of α-tocopherol acetate significantly attenuated the epidermal proliferative response and Stat1 activation suggesting that chrysarobin-mediated generation of ROS may play a role in its effects on Stat1 during tumor promotion. Additional studies are underway to further determine the mechanistic basis for the role of Stat1 in chrysarobin-mediated tumor promotion. Supported by NIH grant CA 76520. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2480.