Abstract
The human sulfatase 1 (hSulf-1) gene encodes an endosulfatase that functions to inhibit the heparin-binding growth factor signaling, including the basic fibroblast growth factor (bFGF)-mediated pathway, by desulfating the cell surface heparan sulfate proteoglycans (HSPGs). bFGF could stimulate cell cycle progression and inhibit cell apoptosis, this biological effect can be reversed by hSulf-1. However, molecular mechanisms have not been fully reported. In the current study, by reactivation of hSulf-1 expression and function in the hSulf-1-negative hepatocellular carcinoma (HCC) cell lines and HCC xenograft tumors, we found that hSulf-1 blocked the bFGF effect on the promotion of cell cycle and inhibition of apoptosis. The bFGF-stimulated activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways was suppressed by hSulf-1, which led to a decreased expression of the target genes Cyclin D1 and Survivin, then finally induced cell cycle arrest and apoptosis in HCC cells. Our data suggested that hSulf-1 may be a suitable target for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Line
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Fibroblast Growth Factor 2 / pharmacology*
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Humans
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Immunohistochemistry
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Mice, Inbred BALB C
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Mice, Nude
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Sulfotransferases / genetics
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Sulfotransferases / metabolism*
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Survivin
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays / methods*
Substances
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Survivin
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Fibroblast Growth Factor 2
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Cyclin D1
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 3
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SULF1 protein, human
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Sulfotransferases