Distinct roles of individual Smads in skin carcinogenesis

Transforming growth factor β (TGFβ) signaling has both tumor suppression and promotion roles. Smads are transcription factors that primarily mediate intracellular signaling for the TGFβ superfamily. Loss of Smad2 and Smad4, but not Smad3 is common in human cancers. Given the complex nature of TGFβ signaling, dissection of the distinct role of each Smad in mediating the multiple functions of TGFβ signaling is warranted. To further analyze Smad deregulation during carcinogenesis, Smad2, Smad3, Smad4, and Smad7 were genetically modified in murine epidermis, and each alteration resulted in distinct skin phenotypes. Based on data from human cancer samples and from experimental models, Smad2 and Smad4 mainly function as tumor suppressors in skin carcinogenesis in vivo, whereas Smad3 and Smad7 may have dual roles in cancer. This review intends to summarize recent advances in the elucidation of the roles of Smad2, Smad3, Smad4, and Smad7 in skin carcinogenesis.