title: Activation of the transforming growth factor-β/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Renumathy
authors.initials: R
authors.lastname: Dhanasekaran
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nakamura
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Oseini
authors.forename: Elif Sezin
authors.initials: ES
authors.lastname: Seven
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Miamen
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.forename: Taofic
authors.initials: T
authors.lastname: Mounajjed
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D051785:Smad Proteins / Q000502:physiology*; D015238:Sulfotransferases / Q000502:physiology*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C486773:Sulf1 protein, mouse; D015238:Sulfotransferases