Smad4 Expression in Hepatocellular Carcinoma Differs by Hepatitis Status

Abstract

Aims: 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. Methods: Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. 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 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). Conclusion: 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.

Significance of pSmad2/3 and Smad4 in hepatitis C virus‐related liver fibrosis and hepatocellular carcinoma

“…In accordance with many other studies (17,18,40), our data demonstrated that Smad4-positive cases, extent of expression, and intensity of staining were significantly higher in CHC and HCC lesions compared to control cases; and higher in HCC lesions compared to CHC lesions. This is in accordance with Yao et al (39) who reported higher Smad4 protein levels in patients with viral hepatitis and they suggested that Smad4 expression might be modulated by hepatitis viruses, and that increased Smad4 expression in patients with viral hepatitis predicts a higher risk for HCC. Howeveron the contrary to our findings -Yao et al (39) found stronger intensity of Smad4 expressions in adjacent tissues compared to HCC.…”

“…Studies indicate that the expression level of Smad4 is closely related to the development, biological features, and prognosis of many kinds of malignant tumors (36)(37)(38). In line with Yao et al (39) results, we found cytoplasmic staining of Smad4 in the hepatocytes.…”

Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas

“…In HCC, SMAD4 mutations are uncommon (> 2%) [COSMIC Database]. However, there are also reports of reduced SMAD4 expression in HCC cells compared to surrounding liver tissue[35]. In contrast, increased expression was reported in subsets of patients with chronic viral hepatitis infection or in association with increased TGF-βRII overexpression, and was linked with poor prognosis[35-37].…”

“…However, there are also reports of reduced SMAD4 expression in HCC cells compared to surrounding liver tissue[35]. In contrast, increased expression was reported in subsets of patients with chronic viral hepatitis infection or in association with increased TGF-βRII overexpression, and was linked with poor prognosis[35-37]. Emerging data regarding inhibitory SMADs (I-SMAD) showed that low levels of SMAD7 correlated with increased recurrence and shorter survival in PDAC and HCC patients[38, 39].…”

Preparation of DOX/BSANP and Its Antitumor Effect on Bel-7404 Liver Cancer Cells in Vitro and in Vivo

“…Its prevalence and mortality rate in China account for 55% and 45%, respectively, of those worldwide [1]. At present, surgical resection still remains the first-line treatment of liver cancer.…”