Activation of the Transforming Growth Factor-beta/SMAD Transcriptional Pathway Underlies a Novel Tumor-Promoting Role of Sulfatase 1 in Hepatocellular Carcinoma

摘要

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- (TGF-)/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on the TGF-/SMAD pathway is functional; overexpression of SULF1 promotes TGF--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- from the cell surface. We also show that SULF1 expression decreases the interaction between TGF-1 and its heparan sulfate proteoglycan sequestration receptor, TGFR3. 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- expression and with several TGF--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- pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC. (Hepatology 2015;61:1269-1283)