Protective Effects of Docosahexaenoic Acid against UVB-induced Mouse Skin Carcinogenesis

Abstract

Exposure to solar radiation, especially ultraviolet B (UVB), is the most prevalent environmental carcinogen that increases the risk of skin cancer. Oxidative stress and persistent inflammation are the key pathologic events in UVB-induced skin photocarcinogenesis. Signal transducer and activator of transcription-3 (STAT3) 3, one of the major redox-sensitive transcription factors, plays an essential role in the pathogenesis of inflammation and subsequent development of skin cancer. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which occur at high levels in some fish oils, are known to possess radical scavenging activity and increase host immunoresponsiveness. The present study was aimed at evaluating the anti-inflammatory and anti-tumor promoting activity of docosahexaenoic acid (DHA), a prototypic ω-3 PUFA, in mouse skin irradiated with UVB. Topical application of DHA (2.5 and 10 µmol) prior to UVB irradiation (180 mJ/cm2) diminished epidermal hyperplasia and formation of 4-hydroxynonenal modified protein and malondialdehyde, the biochemical hallmarks of lipid peroxidation, in HR-1 hairless mouse skin. Pretreatment with DHA inhibited UVB-induced phosphorylation of STAT3 (Tyr705) and expression of its target gene, c-myc in the mouse skin. Moreover, repeated DHA pretreatment until the termination of the experiment at the 23rd week reduced the incidence and the multiplicity of papillomas and squamous cell carcinomas in UVB-induced mouse skin. DHA down-regulates STAT3 activation and c-Myc expression in papillomas as compared to ultraviolet radiation alone. Furthermore, topically applied DHA induced the expression of antioxidant enzymes, heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1 in the mouse skin. Taken together, DHA protected against UVB-induced mouse skin tumor development by blocking STAT3 activation and enhancing inducing antioxidant enzyme expression, suggesting that this ω-3 PUFA has potential for use to ameliorate UVB-induced skin tissue damage and related abnormal disorders including photocarcinogenesis.