title: MYCN-dependent expression of sulfatase-2 regulates neuroblastoma cell survival.
abstract: Heparan sulfate proteoglycans (HSPG) play a critical role in the interaction of tumor cells and their microenvironment. HSPG activity is dictated by sulfation patterns controlled by sulfotransferases, which add sulfate groups, and sulfatases (Sulf), which remove 6-O-sulfates. Here, we report altered expression of these enzymes in human neuroblastoma cells with higher levels of Sulf-2 expression, a specific feature of MYCN-amplified cells (MYCN-A cells) that represent a particularly aggressive subclass. Sulf-2 overexpression in neuroblastoma cells lacking MYCN amplification (MYCN-NA cells) increased their in vitro survival. Mechanistic investigations revealed evidence of a link between Sulf-2 expression and MYCN pathogenicity in vitro and in vivo. Analysis of Sulf-2 protein expression in 65 human neuroblastoma tumors demonstrated a higher level of Sulf-2 expression in MYCN-A tumors than in MYCN-NA tumors. In two different patient cohorts, we confirmed the association in expression patterns of Sulf-2 and MYCN and determined that Sulf-2 overexpression predicted poor outcomes in a nonindependent manner with MYCN. Our findings define Sulf-2 as a novel positive regulator of neuroblastoma pathogenicity that contributes to MYCN oncogenicity. Cancer Res; 74(21); 5999-6009. ©2014 AACR.
authors.affiliation: Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom. Division of Hematology-Oncology, Department of Pediatrics, University of Southern California, Los Angeles, California. The Saban Research Institute of Children's Hospital, Los Angeles, California.
authors.forename: Valeria
authors.initials: V
authors.lastname: Solari
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, University of Southern California, Los Angeles, California. The Saban Research Institute of Children's Hospital, Los Angeles, California.
authors.forename: Lucia
authors.initials: L
authors.lastname: Borriello
authors.affiliation: The Saban Research Institute of Children's Hospital, Los Angeles, California.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Turcatel
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, University of Southern California, Los Angeles, California. Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Sposto
authors.affiliation: The Saban Research Institute of Children's Hospital, Los Angeles, California.
authors.forename: G Esteban
authors.initials: GE
authors.lastname: Fernandez
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, University of Southern California, Los Angeles, California. Department of Pathology, University of Southern California, Los Angeles, California. Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.affiliation: Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Yates
authors.affiliation: Centre for Glycobiology, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom. declerck@usc.edu j.turnbull@liverpool.ac.uk.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, University of Southern California, Los Angeles, California. The Saban Research Institute of Children's Hospital, Los Angeles, California. Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California. declerck@usc.edu j.turnbull@liverpool.ac.uk.
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerck
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013429:Sulfatases; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D019812:Heparan Sulfate Proteoglycans; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases