In addition, some MC1-R variants have been associated to melanoma risk . MITF, on the other hand, is also involved in the regulation of the cell cycle and proliferation, and few variants of the gene have been found in melanoma patients [31, 32]. In particular, MITF(E318K) was reported to represent
a gain-of-function allele for the gene, supporting MITFs role as an oncogene. However, MITFs expression in melanoma metastasis is yet to be clarified, as there are also studies showing that downregulation and ablation of this gene create a more invasive phenotype in vitro  and increase tumor growth in vivo , respectively. The transcription Inhibitors,research,lifescience,medical factor activator protein-2α (AP2α) has been suggested as a major key player in the transition from RGP to VGP . Similar to several other mediators, AP2α also modulates a variety of cellular processes, including cell growth and BIX 01294 in vitro apoptosis. In tumors, AP2α acts as a tumor suppressor, and high cytoplasmatic to nuclear Inhibitors,research,lifescience,medical expression ratio was shown to correlate with poor patients’ prognosis [35, 36]. In particular, the promoters for the adhesion molecule MCAM/MUC18 , which is overexpressed in tumors, and tyrosinase Inhibitors,research,lifescience,medical kinase receptor, c-KIT (silenced
in 70% of metastatic tumors) , have AP2α binding sites. AP2α has been described to directly bind to MCAM/MUC18 promoter and to inhibit its transcription, whereas it promotes c-KIT expression. Therefore, the loss of this transcription factor during melanoma results in Inhibitors,research,lifescience,medical high MCAM/MUC18 levels and c-KIT downregulation. In addition, the loss of AP2α was also appointed as a probable cause for the upregulation of the G-protein-coupled receptor protease activated Inhibitors,research,lifescience,medical receptor-1, PAR-1 [10, 39]. In PAR-1
promoter region, there are two binding complexes for AP2α and SP1. In normal melanocytes, AP2α binds to PAR-1 inhibiting its transcription. However, upon melanoma progression, the levels of AP2α decrease, and SP1 binds to the PAR-1 promoter instead, driving its expression. RAS, phosphoinositide-3 kinase (PI3K), and MAPK STK38 pathways are all signaling events downstream PAR-1, and hence closely related to tumor progression . During the metastatic process, following evasion into the blood circulation, tumor cells adhere to the endothelium at distant sites, and herein adhesion molecules are necessary. Together with selectins, integrins have been found to play crucial roles in these steps. Integrins are a family of transmembrane glycoproteins that mediate cell-cell and cell-matrix adhesion. It is therefore expected that their expression pattern changes during tumor growth, metastasis, and angiogenesis. In particular, αvβ3 and α4β1 (very late activation antigen-4, VLA-4) have been reported as overexpressed in numerous cancer types [41, 42] and have served as therapeutic targets.