Basic-liver, pancreas, and biliary tracthSulf1 sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling☆
Section snippets
Tumor samples
Thirty-one HCC tumors were used for the real-time PCR experiments and 94 HCCs for the loss of heterozygosity (LOH) experiments. For each case, tumor samples with matched adjacent benign tissue were collected during surgical resections at the Mayo Clinic between 1991 and 2001, frozen in liquid nitrogen, and stored at −80°C. Sections from each specimen were examined by a pathologist and graded histologically. The study was approved by the Mayo Clinic Institutional Review Board.
HCC cell lines
The following HCC
Expression of the hSulf1 sulfatase mRNA is decreased in a proportion of primary HCC and HCC cell lines
Our previous results demonstrated down-regulation of hSulf1 in 77% (23/30) of ovarian carcinomas and in the majority of cancer cell lines of ovarian, breast, pancreas, kidney, and liver origin.11, 12 To determine whether hSulf1 was also down-regulated in primary HCCs, we evaluated hSulf1 expression in 31 primary HCCs by quantitative real-time PCR. Twenty-two of the HCCs were randomly selected, and 9 additional tumors were selected based on known LOH at the hSulf1 locus. Of the 31 total HCCs
Discussion
In the present study, we have demonstrated that the newly identified sulfatase gene hSulf1 is down-regulated in approximately 30% of primary HCC tumors and 80% of HCC cell lines and has a growth-inhibitory, proapoptotic function in HCC cell lines. We showed that hSulf1 is localized to the cell surface and has a measurable sulfatase activity in hSulf1-expressing HCC cell lines. We also demonstrated that the substrates of hSulf1 include sulfated heparan sulfate proteoglycans (HSPGs) at the cell
Acknowledgements
The authors thank Kristi Simmons and Eric Bungum for secretarial assistance; Steve Bronk and Drs. Ali Canbay, Hong Cao, Jing Chen, Haidong Dong, Eugenia Guicciardi, and Hajime Higuchi for technical assistance; and Drs. Gregory Gores and Scott Kaufmann for critical review of the manuscript.
References (54)
Epidemiology of hepatocellular carcinoma
Clin Liver Dis
(2001)- et al.
Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States
Hepatology
(2001) Pathogenesis of hepatocellular carcinoma
Clin Liver Dis
(2001)- et al.
Loss of HSulf-1 up-regulates heparin binding growth factor signaling in cancer
J Biol Chem
(2003) - et al.
Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans
J Biol Chem
(2002) - et al.
Differential structural requirements of heparin and heparan sulfate proteoglycans that promote binding of basic fibroblast growth factor to its receptor
J Biol Chem
(1994) - et al.
Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity
J Biol Chem
(1998) - et al.
Cathepsin B contributes to bile salt-induced apoptosis of rat hepatocytes
Gastroenterology
(1997) - et al.
Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism
Cell
(1996) - et al.
Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization
Mol Cell
(2000)
Fibroblast growth factor-2 stimulation of p42/44MAPK phosphorylation and IκB degradation is regulated by heparan sulfate/heparin in rat mammary fibroblasts
J Biol Chem
Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism
J Hepatol
Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines
Hepatology
A matter of life and death
Cancer Cell
Induction of a common pathway of apoptosis by staurosporine
Exp Cell Res
Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysisrelationship to disease stage, tumor size, and cirrhosis
Am J Pathol
Differential effects of heparin saccharides on the formation of specific fibroblast growth factor (FGF) and FGF receptor complexes
J Biol Chem
Distinct role of 2-O-, N-, and 6-O-sulfate groups of heparin in the formation of the ternary complex with basic fibroblast growth factor and soluble FGF receptor-1
Biochem Biophys Res Commun
Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis
J Biol Chem
GLOBOCAN 2000Cancer incidence, mortality and prevalence worldwide, version 1.0
NIH conference. Hepatocellular carcinoma
Ann Intern Med
Carcinogenesis of primary liver malignancies
Langenbecks Arch Surg
Epidemiology of hepatocellular carcinoma
Can J Gastroenterol
Effects of Bcl-2 and Bcl-XL protein levels on chemoresistance of hepatoblastoma HepG2 cell line
Biochem Cell Biol
Genetics of hepatocellular carcinoma
Semin Cancer Biol
Molecular pathogenesis of human hepatocellular carcinoma
Nat Genet
Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization
Cancer Res
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Supported by the National Institutes of Health (CA82862 and CA100882 to L.R.R.), an Industry Research Scholar Award from the Foundation for Digestive Health and Nutrition (to L.R.R.), a Minority Medical Faculty Development Awards from The Robert Wood Johnson Foundation (to L.R.R. and E.L.G.), DOD grant DAMD17-99-1-9504 (to V.S. and D.I.S.), a John W. Anderson Foundation grant (to V.S.), and the Mayo Foundation.
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V.S. and L.R.R. contributed equally to this work.