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

Jin-Ping Lai ¹, Jeremy R Chien , David R Moser

⁰Division of Gastroenterology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Gastroenterology +

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December 31, 2003

View abstract on PubMed

Summary

Down-regulation of hSulf1 in hepatocellular carcinoma (HCC) enhances growth factor signaling and reduces apoptosis. Restoring hSulf1 expression in HCC cells can re-sensitize them to chemotherapy.

Area Of Science

Hepatocellular Carcinoma Research
Molecular Biology
Cancer Signaling Pathways

Background

Heparin-binding growth factors like FGF and HGF are key drivers of hepatocellular carcinoma (HCC) growth.
Cell-surface heparan sulfate proteoglycans (HSPGs) regulate growth factor signaling through sulfation.
The sulfatase hSulf1 is investigated for its role in regulating growth signaling within HCCs.

Purpose Of The Study

To investigate the role of hSulf1 in hepatocellular carcinoma (HCC) growth.
To determine if hSulf1 regulates growth factor signaling pathways in HCC.
To assess the impact of hSulf1 on HCC cell apoptosis and chemoresistance.

Main Methods

Real-time PCR and loss of heterozygosity (LOH) analysis to assess hSulf1 expression in HCC tumors and cell lines.
Immunocytochemistry to determine hSulf1 subcellular localization and HSPG sulfation.
Phospho-specific immunoblotting to examine FGF and HGF signaling.
Cell proliferation assays (trypan blue exclusion, MTT) and apoptosis quantitation (fluorescence microscopy).

Main Results

hSulf1 expression was reduced in 29% of HCCs and 82% of cell lines, with LOH observed in 42% of tumors.
Reduced hSulf1 correlated with increased HSPG sulfation, enhanced FGF/HGF signaling, and elevated HCC cell growth.
Forced hSulf1 expression decreased HSPG sulfation and inhibited growth signaling.
High hSulf1 expression sensitized HCC cells to apoptosis-inducing agents (staurosporine, cisplatin), while low expression conferred resistance.

Conclusions

Down-regulation of hSulf1 contributes to hepatocarcinogenesis by promoting growth factor signaling.
Reduced hSulf1 expression leads to resistance to apoptosis in HCC cells.
Restoring hSulf1 expression can re-sensitize HCC cells to chemotherapy, offering potential therapeutic strategies.

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