Analyses of TGF-β Signal Transduction Mechanisms in Hepatocellular Carcinoma and Applications for its Treatment.

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To clarify the mechanism of resistance to the anti-proliferative effect of TGF-b in human HCC cells, we studied the stimulatory mechanism by tumor-derived TGF-β using HCC-M and HCC-T cell lines. In these cells, tumor-derived TGF-β accelerated their proliferation. Smad 2 was constitutively activated by the autocrine mechanism. This constitutive activation of Smad 2 was, at least in part, due to the lack of induction of antagonistic Smads by TGF-β (Cancer Res. 2000 ; 60 : 1394-1402). Furthermore, we investigated regulatory mechanisms for TGF-β as an autocrine inhibitor using HuH-7 and HepG2 cells. The study demonstrated that HuH-7 and HepG2 cells exhibited only a limited growth inhibitory response to TGF-β in comparison with hepatocytes, because tumor-derived TGF-β induced antagonistic Smad 7, and Smad 7 limited the basal activation levels of R-Smads (Hepatology 2000 ; 32 : 218-227).We also showed that Down-regulation of TGF-β receptor occurred in hepatocytes after chemical insult and TGF-β could not transduce its anti-proliferative signal. Recovery of TGF-β receptor expression causes the signal to transduce to the nucleus at 72 hr. In HSC, whenever TGF-β is increased, TGF-β can transduce its signal for fibronectin production via its receptor, because signaling receptors are expressed constantly (Gut 2000 ; 46 : 719-724, J of Hepatology 2000 ; 32 : 251-260, J of Hepatology 1998 ; 28 : 572-581).