Abstract
Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-β pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. 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 were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG). Patients with hepatitis viral infection, at higher risk for HCC, exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, which is functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker for diagnosis and/or a target to develop therapeutic agents for HCC.
Highlights
Primary hepatocellular carcinoma (HCC), one of the most common malignancies, is a viral infection related cancer
The Smad4 protein is encoded by the DPC4 gene, which is located in chromosome 18q21.1 and thought to be a putative tumor suppressor gene (TSG), while mutating or deleting the Smad4 gene interrupts the transmission of signals from the TGF-β pathway (Hahn et al, 1996a, 1996b; Maurice et al, 2001)
Smad4 expression in patients with viral hepatitis predicts a higher risk for HCC than for those without hepatitis
Summary
Primary hepatocellular carcinoma (HCC), one of the most common malignancies, is a viral infection related cancer. Hepatitis B virus (HBV), hepatitis C virus (HCV), and aflatoxin have been confirmed as the main causes of HCC (Shin et al, 2006; Feitelson and Lee, 2007; Keasler et al, 2007), the mechanisms underlying the malignant transformation of hepatocytes are still largely unknown (Ozturk, 1995). Transforming growth factor beta (TGF-β) has a central role in the growth of hepatocytes (Rossmanith and Schulte-Hermann, 2001), where the Smad family of proteins, Smad, is the key mediator of the TGF-β pathway (Lee et al, 2001; Torbenson et al, 2002; Yakicier et al, 1999; Lönn et al, 2009; Yang and Yang, 2010). Loss or inactivation of Smad is related to pancreatic cancer (Ang et al, 2010; Hahn et al, 1996a, 1996b), colorectal cancer (Ang et al, 2010), and occurs in some cases of extrahepatic cholangiocarcinoma (Argani et al, 2001), gastrointestinal cancers (Lei et al, 1996; Maitra et al, 2000) as well as other malignancies (Schutte et al, 1996; Miyaki and Kuroki, 2003; Waite and Eng, 2003)
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