Role of GalNAc4S-6ST in astrocytic tumor progression

PLoS One. 2013;8(1):e54278. doi: 10.1371/journal.pone.0054278. Epub 2013 Jan 17.

Abstract

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) is the sulfotransferase responsible for biosynthesis of highly sulfated chondroitin sulfate CS-E. Although involvements of CS-E in neuronal cell functions have been extensively analyzed, the role of GalNAc4S-6ST in astrocytic tumor progression remains unknown. Here, we reveal that GalNAc4S-6ST transcripts were detected in astrocytic tumors derived from all 30 patients examined using quantitative reverse transcription-PCR analysis. Patients with high GalNAc4S-6ST mRNA expression had significantly worse outcome compared with patients with low expression, and multivariate survival analysis disclosed that GalNAc4S-6ST is an independent poor prognostic factor for astrocytic tumors. We then tested whether CS-E enhanced haptotaxic migration of glioblastoma U251-MG cells that endogenously express both the CS-E's scaffold tyrosine phosphatase ζ (PTPζ) and GalNAc4S-6ST, in the presence of CS-E's preferred ligands, pleiotrophin (PTN) or midkine (MK), using a modified Boyden chamber method. Haptotaxic stimulation of cell migration by PTN was most robust on control siRNA-transfected U251-MG cells, while that enhancing effect was cancelled following transduction of GalNAc4S-6ST siRNA. Similar results were obtained using MK, suggesting that both PTN and MK enhance migration of U251-MG cells by binding to CS-E. We also found that PTPζ as well as PTN and MK were frequently expressed in astrocytic tumor cells. Thus, our findings indicate that GalNAc4S-6ST mRNA expressed by astrocytic tumor cells is associated with poor patient prognosis likely by enhancing CS-E-mediated tumor cell motility in the presence of PTN and/or MK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Astrocytoma / genetics*
  • Astrocytoma / metabolism
  • Astrocytoma / pathology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Chondroitin Sulfates / metabolism
  • Cytokines / metabolism
  • Disease Progression
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • In Situ Hybridization
  • Male
  • Middle Aged
  • Midkine
  • Multivariate Analysis
  • Prognosis
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfotransferases / genetics*
  • Sulfotransferases / metabolism
  • Survival Analysis

Substances

  • Carrier Proteins
  • Cytokines
  • pleiotrophin
  • Midkine
  • Chondroitin Sulfates
  • N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase
  • Sulfotransferases
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research 18390113 from the Japan Society for the Promotion of Science (to J.N.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.