Taking into account that Smad6 is at the crossroad of many signaling pathways, being regulated not only by family members of bone morphogenetic protein (BMP) and TGFβ, but also by epidermal growth factor and Ras/MAPK [6,7,37], its expression may be key to shift signaling from oncogenesis to tumor supression, towards or against proliferation, independent of Smad3 and Smad4, at least in oral SCC (Figure 4). This evidence concerns the gene SMAD3 and neoplasm.