Activation of the transforming growth factor-β/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma.

Hepatology (Baltimore, Md.) 2015 Apr

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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-β (TGF-β)/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on the TGF-β/SMAD pathway is functional; overexpression of SULF1 promotes TGF-β-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-β from the cell surface. We also show that SULF1 expression decreases the interaction between TGF-β1 and its heparan sulfate proteoglycan sequestration receptor, TGFβR3. 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-β expression and with several TGF-β-related epithelial-mesenchymal transition genes in human HCC. Our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGF-β pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC. © 2014 by the American Association for the Study of Liver Diseases.

Citation

Renumathy Dhanasekaran, Ikuo Nakamura, Chunling Hu, Gang Chen, Abdul M Oseini, Elif Sezin Seven, Alexander G Miamen, Catherine D Moser, Wei Zhou, Toin H van Kuppevelt, Jan M van Deursen, Taofic Mounajjed, Martin E Fernandez-Zapico, Lewis R Roberts. Activation of the transforming growth factor-β/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2015 Apr;61(4):1269-83