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MYCN-Dependent Expression of Sulfatase-2 Regulates Neuroblastoma Cell Survival

2014; American Association for Cancer Research; Volume: 74; Issue: 21 Linguagem: Inglês

10.1158/0008-5472.can-13-2513

1538-7445

Valeria Solari, Lucia Borriello, Gianluca Turcatel, Hiroyuki Shimada, Richard Sposto, G. Esteban Fernández, Shahab Asgharzadeh, Edwin A. Yates, Jeremy E. Turnbull, Yves A. DeClerck,

Neonatal Respiratory Health Research

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.