Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma


Heidari-Hamedani G., Vives R. R. , Seffouh A., Afratis N. A. , Oosterhof A., van Kuppevelt T. H. , ...More

CELLULAR SIGNALLING, vol.27, no.10, pp.2054-2067, 2015 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 27 Issue: 10
  • Publication Date: 2015
  • Doi Number: 10.1016/j.cellsig.2015.07.017
  • Title of Journal : CELLULAR SIGNALLING
  • Page Numbers: pp.2054-2067
  • Keywords: Syndecan-1, Malignant mesothelioma, Transcription factor, Mitogen-activated protein kinase (MAPK), Receptor tyrosine kinase, CAPILLARY-ELECTROPHORESIS, CELL-PROLIFERATION, HUMAN BREAST, GROWTH, EXPRESSION, BIOSYNTHESIS, BINDING, DIFFERENTIATION, TUMORIGENESIS, PROTEOGLYCANS

Abstract

Syndecan-1 is a proteoglycan that acts as co-receptor through its heparan sulfate (HS) chains and plays important roles in cancer. HS chains are highly variable in length and sulfation pattern. This variability is enhanced by the SULF1/2 enzymes, which remove 6-O-sulfates from HS. We used malignant mesothelioma, an aggressive tumor with poor prognosis, as a model and demonstrated that syndecan-1 over-expression down-regulates SULF1 and alters the HS biosynthetic machinery. Biochemical characterization revealed a 2.7-fold reduction in HS content upon syndecan-1 over-expression, but an overall increase in sulfation. Consistent with low SULF1 levels, trisulfated disaccharides increased 2.5-fold. ERK1/2 activity was enhanced 6-fold. Counteracting ERK activation, Akt, WNK1, and c-Jun were inhibited. The net effect of these changes manifested in G1 cell cycle arrest. Studies of pleural effusions showed that SULF1 levels are lower in pleural malignancies compared to benign conditions and inversely correlate with the amounts of syndecan-1, suggesting important roles for syndecan-1 and SULF1 in malignant mesothelioma. (C) 2015 The Authors. Published by Elsevier Inc.