Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2

Summary In the liver, derangement of TGF-β signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), but the mechanism is not clear. We report here that forced expression of a major TGF-β signaling transducer, Smad3, reduces susceptibility to HCC in a chemically induced murine model. This protection is conferred by Smad3's ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. We also show that the proapoptotic activity of Smad3 requires both input from TGF-β signaling and activation of p38 MAPK, which occurs selectively in the liver tumor cells. Thus, Smad3 enables the tumor suppression function of TGF-β by serving as a physiological mediator of TGF-β-induced apoptosis.