Roles of TGFβ signaling Smads in squamous cell carcinoma

Smad proteins are classified in different groups based on their functions in mediating transforming growth factor β (TGFβ) superfamily components. Smad1/5/8 mainly mediate bone morphogenetic proteins (BMP) pathway and Smad2/3 mainly mediate TGFβ pathway. Smad4 functions as common Smad to mediate both pathways. Previous studies showed many members of TGFβ superfamily play a role in carcinogenesis. The current review focuses on the role of TGFβ signaling Smads in squamous cell carcinomas (SCCs). TGFβ signaling inhibits early tumor development, but promotes tumor progression in the late stage. Although Smad2, Smad3 and Smad4 are all TGFβ signaling Smads, they play different roles in SCCs. Genetically, Smad2 and Smad4 are frequently mutated or deleted in certain human cancers whereas Smad3 mutation or deletion is infrequent. Genetically engineered mouse models with these individual Smad deletions have provided important tools to identify their diversified roles in cancer. Using these models, we have shown that Smad4 functions as a potent tumor suppressor and its loss causes spontaneous SCCs development; Smad2 functions as a tumor suppressor and its loss promotes SCC formation initiated by other genetic insults but is insufficient to initiate tumor formation. In contrast, Smad3 primarily mediates TGFβ-induced inflammation. The functions of each Smad also depends on the presence/absence of its Smad partner, thus need to be interpreted in a context-specific manner.