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In liver, TGF-beta limits regenerative tissue growth after injury by inhibiting DNA synthesis and inducing apoptosis. Derangement of TGF-beta signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), a common visceral malignancy. However, the exact mechanism by which TGF-beta induces apoptosis and suppresses liver tumorigenesis is not clear. We report here that ectopic expression of a major TGF-beta signaling transducer Smad3 in liver reduces susceptibility to HCC in a chemically induced murine model. This protection is conferred by the ability of Smad3 to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 P2 promoter. Surprisingly, ectopic expression alone is not sufficient to activate the pro-apoptotic activity of Smad3 in normal hepatocytes; this is even true for Smad3SD, a mutant that is enriched in the nucleus due to two aspartic substitutions at the c-terminus. Additional input from p38 MAPK kinase, which is activated in liver tumor cells but not in normal hepatocytes, is required. Thus, Smad3 is a physiological mediator of TGF-beta-induced apoptosis and a suitable candidate of gene therapeutic agent for treating currently incurable HCC.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]