Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy

The transforming growth factor (TGF)-β signaling pathway controls many cellular processes, including proliferation, differentiation, and apoptosis. Abnormalities in the TGF-β signaling pathway and its components are closely related to the occurrence of many human diseases, including cancer. Mothers against decapentaplegic homolog 4 (Smad4), also known as deleted in pancreatic cancer locus 4, is a typical tumor suppressor candidate gene locating at q21.1 of human chromosome 18 and the common mediator of the TGF-β/Smad and bone morphogenetic protein/Smad signaling pathways. It is believed that Smad4 inactivation correlates with the development of tumors and stem cell fate decisions. Smad4 also interacts with cytokines, miRNAs, and other signaling pathways, jointly regulating cell behavior. However, the regulatory function of Smad4 in tumorigenesis, stem cells, and drug resistance is currently controversial. In addition, Smad4 represents an attractive therapeutic target for cancer. Elucidating the specific role of Smad4 is important for understanding the mechanism of tumorigenesis and cancer treatment. Here, we review the identification and characterization of Smad4, the canonical TGF-β/Smad pathway, as well as the multiple roles of Smad4 in tumorigenesis, stem cells, and drug resistance. Furthermore, we provide novel insights into the prospects of Smad4-targeted cancer therapy and the challenges that it will face in the future.