Abstract 834: Constitutive omega-3 fatty acid production in fat-1 transgenic mice protects against UVB-induced skin inflammation and carcinogenesis

Abstract

Abstract Exposure to solar radiation, especially ultraviolet B (UVB), is the most prevalent cause of skin photocarcinogenesis. Omega-6 (ù-6) and omega-3 (ù-3) polyunsaturated fatty acids (PUFAs) are known to have opposite effects on the inflammatory and carcinogenesis processes. Generally, ù-6 PUFAs promote inflammation and tumor development, whereas ù-3 PUFAs possess anti-inflammatory as well as antioxidative activity and enhance host immune response. In the present study, we investigated the protective effects of ù-3 PUFAs on UVB-induced skin inflammation and carcinogenesis using fat-1 transgenic mice harboring ù-3 desaturase gene capable of converting ù-6 to ù-3 PUFAs. The ù-3/ù-6 PUFA ratio was significantly higher in the dorsal skin of fat-1 mice than that in the wild-type (WT) C57BL/6 mice. In comparison to WT animals, fat-1 mice expressed heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1 and their mRNA transcripts to a greater extent, which was attributable to the elevated activation of nuclear factor erythroid-related factor-2 (Nrf2) responsible for upregulation of cytoprotective and stress-responsive proteins. Upon single exposure to UVB (500 mJ/cm2) irradiation, fat­1 mice exhibited a significantly lower degree of skin inflammation and phototoxicity and the expression of the pro-inflammatory enzyme, cyclooxygenases-2 (COX-2) as compared to those observed in WT mouse skin. The protection of fat-1 mice from UVB-induced skin inflammation was associated with decreased phosphorylation of signal transducer and activator of transcription 3 (STAT3), one of the major redox-sensitive transcription factors, whose overactivation is implicated in the pathogenesis of inflammation and subsequent development of skin cancer. To determine whether the elevated ù-3 PUFA level also protects against skin papillomagenesis, hairless fat-1−/− albino and fat-1+/− albino mice were generated by cross-breeding of male fat-1+/− transgenic mice with female SKH-1 hairless albino mice. After repeated UVB irradiation (180 mJ/cm2) thrice a week for 23 weeks, the incidence and the multiplicity of papillomas were markedly reduced in the fat-1+/− albino group as compared to the fat-1−/− albino group. Moreover, the expression of COX-2 and activation of STAT3 in papillomas from fat-1+/− albino mice were significantly lower than those found in UVB-irradiated fat-1−/− albino mice. Taken together, our results indicate that functional fat-1 potentiates cellular defense against UVB-induced skin inflammation and tumor development through elevation of Nrf2-mediated upregulation of cytoprotective gene expression. Citation Format: Hye-Won Yum, Joydeb Kumar Kundu, Yong-Yeon Cho, Young-Joon Surh. Constitutive omega-3 fatty acid production in fat-1 transgenic mice protects against UVB-induced skin inflammation and carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 834.