Application of tumor promoters to initiated cells can induce epigenetic changes in the skin which culminate into visible clonal outgrowths known as papillomas [5–7]. Although the exact mechanism of action of tumor promotion remains unclear, sustained hyperplasia and cellular proliferation in the epidermis correlates with the tumor promoting activity. Moreover, treatment

with tetradecanoyl phorbol acetate (TPA) can alter signaling of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (Stat3) signaling in the process of skin carcinogenesis [8]. Stat3 is a transcription factor that plays a critical role in the control of cell proliferation, survival and angiogenesis, all hallmarks of malignancy [9]. Stat3 activity is constitutive Defactinib cost in several malignant cell types and is required for initiation, promotion and progression to a more malignant phenotype in squamous cell carcinomas of the skin (SCC) [8, 10–15]. The critical role of Stat3 in

skin tumor development was further supported by data obtained from the K5.Stat3C transgenic mouse model in which the DiGiovanni and Clifford research groups expressed the Stat3C protein in skin under the control of the keratin-5 promoter [11]. Stat3C is a constitutively active mutant MDV3100 of Stat3 that dimerizes through formation of covalent disulfide linkages between cysteines instead of phosphotyrosines [16]. These mice have a skin phenotype Silibinin closely resembling psoriasis in humans and, when IACS-10759 datasheet subjected to the two-stage skin chemical carcinogenesis protocol, rapidly developed carcinomas, bypassing the papilloma stage

that is normally observed in this model [17]. The transcription factor NF-κB is also activated during inflammation and carcinogenesis [18]. The activated form of NF-κB triggers transcription of specific genes involved in proliferation (cyclin D1, c-myc), angiogenesis (VEGF), antiapoptosis (survivin, BclXL, FLIP) and invasion (MMP9, ICAM-1) proteins [19]. NF-κB activation has been strongly implicated in many types of cancer [18] including skin SCCs [20]. Ablation of β-catenin in murine skin grafts resulted in up-regulation of NF-κB target genes [21]. The skin grafts, which resembled human grade III skin SCCs, were hyperproliferative, the layers of epidermis were disorganized, and contained invasive keratinocytes [21]. Kobielak and Fuchs analyzed human skin SCCs and found 33/40 with low/no β-catenin, and nuclear, activated NF-κB, also characterized by inflammation and interestingly, nuclear phosphorylated Stat3 [21]. Finally, many NF-κB regulated genes are also induced by Stat3 and the interaction between these proteins and their signaling pathways may be involved in the different phases of skin carcinogenesis. Non-specific drug-related side effects of pharmaceuticals hamper their clinical efficacy and underscore the need for investigating better treatment options.