Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: Resistance mechanism to transforming growth factor-β

BACKGROUND/AIMS: Smad7 is an inhibitory Smad of the transforming growth factor (TGF)-beta signaling pathway. To study resistance mechanisms to antiproliferating effect of TGF-beta in human multistep hepatocarcinogenesis, Smad7, Smad4, TGF-beta1 and TGF-beta receptor II were investigated. METHODOLOGY: Smad7 and Smad4 were evaluated in 15 low-grade dysplastic nodules (DNs), 9 high-grade DNs, 6 early hepatocellular carcinomas (eHCCs) and 41 advanced HCCs by immunohistochemistry and in 37 HCCs and corresponding non-HCCs with fresh tissue, the mRNAs of TGF-beta1 and TGF-beta receptor II were analyzed by RT-PCR. RESULTS: Smad7 immunoreactivity in tumor cells was found in 25 (61%) advanced HCCs, in contrast to none of DNs and eHCCs. Smad7 expression was significantly higher in advanced HCCs with increased TGF-beta1 or no decrease of TGF-beta receptor II compared to those of corresponding non-HCCs (p=0.044, p=0.027). Smad4 expression in stellate cells was present in 28 (68%) advanced HCCs, which was higher in smaller sized and better differentiated HCCs. CONCLUSIONS: Smad7, expressed in tumor cells, is considered to be one of resistance mechanisms to increased TGF-beta1 in late stage hepatocarcinogenesis, especially in advanced HCCs without reduced TGF-beta receptor II. Smad4, in stellate cells of HCCs, might be involved in the host resistance to hepatocarcinogenesis.ope