Abstract 4570: Genetic deletion of TNFα in mice inhibits UVR-induced development of cutaneous squamous cell carcinomas via suppression of its own receptors and associated signals to epidermal cell survival

Abstract

Abstract Skin cancer is the second most common malignancy encountered in the U.S. with an expected diagnosis of 1.3 million new cases of non-melanoma skin cancer each year. Cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most common non-melanoma forms of human skin cancer. BCC is rarely life threatening because it is slow growing and is mostly localized. SCC, unlike BCC, invades the nearby tissue. Chronic exposure to ultraviolet radiation (UVR) is the most common etiologic factor linked to the development of cutaneous SCC. PKCϵ transgenic mice provide a unique model to investigate the molecular basis of the development of SCC. PKC is a major intracellular receptor for the mouse skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). PKCϵ is among six isoforms (α, δ, ϵ, η, μ, ζ) expressed in the mouse skin. To determine the in vivo functional specificity of PKCϵ in mouse skin carcinogenesis, we generated FVB/N PKCϵ transgenic mouse lines 224 and 215 that overexpress approximately 8- and 18-fold respectively PKCϵ protein over endogenous levels in basal epidermal cells. We observed that epidermal PKCϵ level dictates the susceptibility of transgenic mice to the development of SCC elicited by either the repeated exposure to UVR or using the DMBA-TPA tumor promotion protocol. Our earlier studies to elucidate mechanisms of PKCϵ-mediated development of SCC indicated an elevated release of cytokine TNFα. To conclusively determine whether TNFα is essential for the development of SCC in PKCϵ transgenic mice, we generated TNFα-knockout//PKCϵ transgenic mice by crossbreeding TNFα knockout mice with PKCϵ transgenic mice. We now present that deletion of both TNFα alleles in PKCϵ transgenic mice significantly (p = 0.0023) inhibited the development of cutaneous SCC by repeated UVR exposures. PKCϵ overexpressing mice deficient in TNFα elicited both increase in SCC latency (21 weeks) and decrease in SCC incidence (55%). Inhibition of SCC development in TNFα-knockout//PKCϵ transgenic mice accompanied by: 1) suppression of the expression levels of TNFα receptors TNFRI and TNFRII, 2) inhibition of the activation of transcription factors Stat3 and NF-κB, and 3) decreased expression levels of cell proliferation marker ornithine decarboxylase and metastatic markers MMP9 and MMP7. In summary, our results indicate that deletion of TNFα in mice inhibits UVR-induced development of cutaneous SCC probably via suppression of its own receptors and associated signals to epidermal cell survival pathways. (Support: NIH Grant CA102431) Citation Format: Ashok Singh, Anupama Singh, Samuel J. Bauer, Ajit K. Verma. Genetic deletion of TNFα in mice inhibits UVR-induced development of cutaneous squamous cell carcinomas via suppression of its own receptors and associated signals to epidermal cell survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4570. doi:10.1158/1538-7445.AM2015-4570