We speculate that in normal conditions, Smad6 transiently binds PIAS3 in nuclei and regulates the PIAS3–STAT3 complex at an appropriate level and time, thus precisely maintaining STAT3 at a reasonable level; however, in cancer-inducing conditions, increased Smad6–PIAS3 interaction destroys the regulation balance and results in aberrant STAT3 transcriptional activation, as well as other oncoproteins deregulation. This evidence concerns the gene SMAD6 and cancer.