Aims: Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viralinfection. Smad4 is known to mediate the TGF-β pathway to suppress tumorigenesis. However, the function ofSmad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or withouthepatitis virus infection and adjacent normal-appearing liver. Methods: Samples from HCC patients wereanalyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Westernblotting. Results: We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues.Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues werepositively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those withoutvirus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to functionas a tumor suppressor gene (TSG). Conclusion: Patients with hepatitis viral infection, at higher risk for HCC,exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, whichis functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker fordiagnosis and/or a target to develop therapeutic agents for HCC.
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