Strong Smad4 Expression Correlates with Poor Prognosis After Surgery in Patients with Hepatocellular Carcinoma

As a pleiotropic cytokine, transforming growth factor-beta (TGF-beta) controls the functions of proliferation, adhesion, and differentiation, and contributes to cancer promotion and suppression. Moreover, it is related to the epithelial-mesenchymal transition process and T cell differentiation associated with inflammation. The Smad4 protein is the downstream mediator of TGF-beta. In this study, we examined the relationship between Smad4 expression and clinicopathological features in patients with hepatocellular carcinoma (HCC). Expression of Smad4 was assessed in five HCC cell lines and in paired cancerous and noncancerous tissues in three patients with HCC, using Western blotting analysis. Moreover, Smad4 expression in 121 HCC patients was evaluated by using immunohistochemistry. Only the Li7 and HT17 cell lines expressed the Smad4 protein. All human samples expressed the protein. Immunohistochemistry showed that Smad4 expression tended to be strong in small HCC nodules less than 45 mm in diameter (P = 0.06) and in the infiltrated part of the tumor capsule. Postoperative survival analysis indicated that HCC patients with strong Smad4 expression had shorter disease-specific survival than those with weak expression (P = 0.04). Multivariate analysis also showed that Smad4 expression could be one predictor of prognosis, but the correlation was not significant (P = 0.07). Although TGF-beta/Smad4 signaling may have various biological effects on human malignancies, strong Smad4 expression in HCC is likely to suggest poor prognosis. The information has implications for predicting HCC prognosis and developing targeted therapeutics.