Role of GalNAc4S-6ST in astrocytic tumor progression

• Published in: PloS one Vol. 8; no. 1; p. e54278
• Main Authors: Kobayashi, Tatsuya, Yan, Huimin, Kurahashi, Yasuhiro, Ito, Yuki, Maeda, Hiroshi, Tada, Tsuyoshi, Hongo, Kazuhiro, Nakayama, Jun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.01.2013; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Astrocytoma - genetics; Astrocytoma - metabolism; Astrocytoma - pathology; Biology; Biosynthesis; Bone cancer; Bone marrow; Boyden chamber; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain research; Carrier Proteins - metabolism; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Child; Child, Preschool; Chondroitin sulfate; Chondroitin Sulfates - metabolism; Comparative analysis; Cytokines - metabolism; Disease Progression; Female; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioblastoma; Gliomas; Growth factors; Hospitals; Humans; In Situ Hybridization; Laboratories; Male; Medical prognosis; Medicine; Metastasis; Middle Aged; Midkine; Multivariate Analysis; N-Acetylgalactosamine; Neurosurgery; Pathology; Patients; Phosphatase; Phosphatases; Physiological aspects; Pleiotrophin; Prognosis; Protein-tyrosine-phosphatase; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Reverse transcription; RNA; Robust control; siRNA; Sulfates; Sulfotransferase; Sulfotransferases - genetics; Sulfotransferases - metabolism; Survival Analysis; Tumor cells; Tumors; Tyrosine; University graduates; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054278

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.