SMAD4 and cancer: Functionally, TGF-β inhibited proliferation and tumorigenesis process; however, during colon cancer cells development, TGF-β signaling was to suppress the effect of tumor suppressor so that TGF-β (TGFβR1 and TGFβR2) or intracellular mediator of SMAD (SMAD4, SMAD2, and SMAD3) were failed in inactivating cancer cells (Yushan et al., 2018).