Abstract 2109: Tumor progression locus 2 (Tpl2) knockout mice have a dysregulation in COX-2 signaling in two-stage skin carcinogenesis

Abstract

Abstract Skin cancer is the most common form of cancer in the United States, with an estimated two million cases diagnosed annually. Inflammation is believed to be a critical component in skin cancer progression, and therefore understanding genes controlling inflammation is beneficial. MAP3K8 (Tpl2) is a protein kinase in the MAP Kinase signal transduction cascade. Previous research using a two-stage skin carcinogenesis model has revealed that Tpl2 -/- mice have significantly higher tumor incidence and inflammation than wild-type (WT) controls. Mechanistically, dysregulation in NF-κB signaling is a major contributor to the high degree of inflammation and tumorigenesis found in the Tpl2 -/- mice. Knockout animals have heightened NF-κB reporter activity, increased NF-κB dependent edema, and increased NF-κB nuclear localization. This study investigates how cyclooxygenase-2 (COX-2), an NF-κB regulated gene known to contribute to skin carcinogenesis, and COX-2 downstream factors might play a role in inflammation-mediated skin carcinogenesis in Tpl2 -/- mice. Keratinocytes from newborn WT or Tpl2 -/- mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for varying times over 24 hours. Western analysis revealed significant differences in COX-2 and COX-2 dependent prostanoids and prostanoid receptors. Additionally, in vivo experiments confirmed that COX-2 and COX-2 downstream factors were elevated in TPA-treated Tpl2 -/- skin, as well as in papillomas and squamous cell carcinomas from Tpl2-/- mice. These experiments illustrate that COX-2 induction in the absence of Tpl2 may be responsible for the increased tumorigenesis found in Tpl2-/- mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2109. doi:10.1158/1538-7445.AM2011-2109