Role of GalNAc4S-6ST in Astrocytic Tumor ProgressionReportar como inadecuado




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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.



Autor: Tatsuya Kobayashi, Huimin Yan, Yasuhiro Kurahashi, Yuki Ito, Hiroshi Maeda, Tsuyoshi Tada, Kazuhiro Hongo, Jun Nakayama

Fuente: http://plos.srce.hr/



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