hSulf1 Sulfatase Promotes Apoptosis of Hepatocellular Cancer Cells by Decreasing Heparin-Binding Growth Factor Signaling

Jin Ping Lai, Jeremy R. Chien, David R. Moser, Julie K. Staub, Ileana Aderca, Damian P. Montoya, Tori A. Matthews, David M. Nagorney, Julie M. Cunningham, David I. Smith, Eddie L. Greene, Viji Shridhar, Lewis R. Roberts

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117 Scopus citations

Abstract

Background & 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.

Original languageEnglish (US)
Pages (from-to)231-248
Number of pages18
JournalGastroenterology
Volume126
Issue number1 SUPPL. 1
DOIs
StatePublished - Jan 2004

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Lai, J. P., Chien, J. R., Moser, D. R., Staub, J. K., Aderca, I., Montoya, D. P., Matthews, T. A., Nagorney, D. M., Cunningham, J. M., Smith, D. I., Greene, E. L., Shridhar, V., & Roberts, L. R. (2004). hSulf1 Sulfatase Promotes Apoptosis of Hepatocellular Cancer Cells by Decreasing Heparin-Binding Growth Factor Signaling. Gastroenterology, 126(1 SUPPL. 1), 231-248. https://doi.org/10.1053/j.gastro.2003.09.043