hSulf1 Sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling

Gastroenterology. 2004 Jan;126(1):231-48. doi: 10.1053/j.gastro.2003.09.043.


Background and aims: The heparin-binding growth factors fibroblast growth factor (FGF) and hepatocyte growth factor (HGF) are potent mitogens for hepatocellular carcinomas (HCCs). Heparin-binding growth factor signaling is regulated by sulfation of cell-surface heparan sulfate proteoglycans (HSPGs). We hypothesized that hSulf1, a recently described sulfatase, regulates growth signaling in HCCs.

Methods: Expression of hSulf1 in human HCC tumors was determined by real-time PCR. Down-regulation of hSulf1 expression was investigated by analyzing loss of heterozygosity (LOH) at the hSulf1 locus and the effect of the DNA methylation inhibitor 5-aza-deoxycytidine on hSulf1 expression. The subcellular location of hSulf1 and sulfation state of cell-surface HSPGs were assessed by immunocytochemistry. FGF and HGF signaling was examined by phospho-specific immunoblot analysis. Cell growth was measured by trypan blue exclusion, and the MTT assay and apoptosis were quantitated by fluorescence microscopy.

Results: hSulf1 expression was decreased in 29% of HCCs and 82% of HCC cell lines. There was LOH at the hSulf1 locus in 42% of HCCs. Treatment with 5-aza-deoxycytidine reactivated hSulf1 expression in hSulf1-negative cell lines. Low hSulf1-expressing cells showed increased sulfation of cell-surface HSPGs, enhanced FGF and HGF-mediated signaling, and increased HCC cell growth. Conversely, forced expression of hSulf1 decreased sulfation of cell-surface HSPGs and abrogated growth signaling. HCC cells with high-level hSulf1 expression were sensitive to staurosporine- or cisplatin-induced apoptosis, whereas low expressing cells were resistant. Transfection of hSulf1 into hSulf1-negative cells restored staurosporine and cisplatin sensitivity.

Conclusions: Down-regulation of hSulf1 contributes to hepatocarcinogenesis by enhancing heparin-binding growth factor signaling and resistance to apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology*
  • Cell Division
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cisplatin / pharmacology
  • DNA Methylation
  • Fibroblast Growth Factor 2 / metabolism*
  • Heparitin Sulfate / metabolism
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology*
  • Loss of Heterozygosity
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Signal Transduction*
  • Staurosporine / pharmacology
  • Sulfates / metabolism
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism*


  • RNA, Messenger
  • Sulfates
  • Fibroblast Growth Factor 2
  • Hepatocyte Growth Factor
  • Heparitin Sulfate
  • SULF1 protein, human
  • Sulfotransferases
  • Staurosporine
  • Cisplatin