| First Author | Dhanasekaran R | Year | 2015 |
| Journal | Hepatology | Volume | 61 |
| Issue | 4 | Pages | 1269-83 |
| PubMed ID | 25503294 | Mgi Jnum | J:317287 |
| Mgi Id | MGI:6851857 | Doi | 10.1002/hep.27658 |
| Citation | Dhanasekaran R, et al. (2015) Activation of the transforming growth factor-beta/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. Hepatology 61(4):1269-83 |
| abstractText | UNLABELLED: In vitro studies have proposed a tumor suppressor role for sulfatase 1 (SULF1) in hepatocellular carcinoma (HCC); however, high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1-Tg), we assessed the effects of SULF1 on the diethylnitrosamine model of liver carcinogenesis. Sulf1-Tg mice show a higher incidence of large and multifocal tumors with diethylnitrosamine injection compared to wild-type mice. Lung metastases were found in 75% of Sulf1-Tg mice but not in wild-type mice. Immunohistochemistry, immunoblotting, and reporter assays all show a significant activation of the transforming growth factor-beta (TGF-beta)/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on the TGF-beta/SMAD pathway is functional; overexpression of SULF1 promotes TGF-beta-induced gene expression and epithelial-mesenchymal transition and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGF-beta from the cell surface. We also show that SULF1 expression decreases the interaction between TGF-beta1 and its heparan sulfate proteoglycan sequestration receptor, TGFbetaR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence-free survival (hazard ratio 4.1, 95% confidence interval 1.9-8.3; P = 0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGF-beta expression and with several TGF-beta-related epithelial-mesenchymal transition genes in human HCC. CONCLUSION: Our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGF-beta pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC. |
