SMAD4 and neoplasm: While the relationship between WWOX and SMAD4 is synergistic, leading to increased apoptosis and tumor suppression, the physical interaction between WWOX and SMAD3 is antagonistic and has been shown to result in the later cytoplasmic sequestration of SMAD3 and reduced transcriptional activity.44 Our current findings show that this inhibitory effect extends further than was previously known, by showing that miR-146a, an effector miRNA of WWOX, targets SMAD3 thus contributing to its anti-metastatic function.