Abstract 3082: Epidermal-specific overexpression of T-cell protein tyrosine phosphatase in mouse attenuates chemically-induced skin carcinogenesis

Abstract

Abstract Tyrosine phosphorylation signaling, which is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is critical in maintaining cellular homeostasis. The aberrant increase of tyrosine phosphorylation by mutation and/or overexpression of PTKs can contribute to skin carcinogenesis. While PTKs have been extensively studied in skin carcinogenesis, PTPs have not been studied due to their inactivation by environmental toxicants. Our recent studies showed that T-cell protein tyrosine phosphatase (TC-PTP; encoded by Ptpn2) deficiency in mouse epidermis significantly increased skin tumor formation, demonstrating TC-PTP deficiency predisposes mice to skin carcinogenesis. To further examine the tumor suppressive role of TC-PTP in skin carcinogenesis, we generated epidermal-specific TCPTP-overexpressing (K5HA.Ptpn2) transgenic mice. TC-PTP overexpression led to sensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP overexpression in epidermis significantly reduced epidermal thickness and hyperproliferation compared to wild-type control following treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, TC-PTP overexpression significantly induced epidermal differentiation following TPA treatment as evidenced by the increased expression of epidermal differentiation markers loricrin, involucrin, keratin 10, and transglutaminase 5 in comparison to control. Two-stage skin carcinogenesis analysis using a DMBA/TPA regimen clearly revealed that K5HA.Ptpn2 mice exhibited delayed tumor development and significantly reduced tumor numbers compared to control mice. Taken together, our results suggest that TC-PTP is a potential therapeutic target for the prevention of skin cancer given its ability to promote epidermal apoptosis and differentiation and inhibit epidermal proliferation. Citation Format: Mihwa Kim, Liza D. Morales, Iksoon Jang, Andrew Tsin, Dae Joon Kim. Epidermal-specific overexpression of T-cell protein tyrosine phosphatase in mouse attenuates chemically-induced skin carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3082.