title: Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma.
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.
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Stockholm, Sweden. Electronic address: Ghazal.heidari.hamedani@ki.se.
authors.forename: Ghazal
authors.initials: G
authors.lastname: Heidari-Hamedani
authors.affiliation: University of Grenoble Alpes, IBS, F-38044 Grenoble, France; CNRS, IBS, F-38044 Grenoble, France; CEA, IBS, F-38044 Grenoble, France.
authors.forename: Romain R
authors.initials: RR
authors.lastname: Vivès
authors.affiliation: University of Grenoble Alpes, IBS, F-38044 Grenoble, France; CNRS, IBS, F-38044 Grenoble, France; CEA, IBS, F-38044 Grenoble, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Seffouh
authors.affiliation: University of Patras, Department of Chemistry, Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Lab. of Biochemistry, Patras, Greece.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Afratis
authors.affiliation: Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Department of Biochemistry, Nijmegen, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: Oosterhof
authors.affiliation: Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, Department of Biochemistry, Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: University of Patras, Department of Chemistry, Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Lab. of Biochemistry, Patras, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: Eskisehir Osmangazi University Medical Faculty, Department of Chest Diseases, Eskisehir, Turkey.
authors.forename: Muzaffer
authors.initials: M
authors.lastname: Metintas
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hjerpe
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Stockholm, Sweden.
authors.forename: Katalin
authors.initials: K
authors.lastname: Dobra
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Stockholm, Sweden.
authors.forename: Tünde
authors.initials: T
authors.lastname: Szatmári
mesh_terms: D053898:Biosynthetic Pathways; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality; D008654:Mesothelioma / Q000378:metabolism* / Q000401:mortality; D000086002:Mesothelioma, Malignant; D016066:Pleural Effusion, Malignant / Q000378:metabolism; D016016:Proportional Hazards Models; D015398:Signal Transduction; D015238:Sulfotransferases / Q000378:metabolism; D053668:Syndecan-1 / Q000502:physiology*
chemical_list: D006497:Heparan Sulfate; D015238:Sulfotransferases; D053668:Syndecan-1; C508241:SDC1 protein, human; C470791:SULF1 protein, human
keywords: Malignant mesothelioma; Mitogen-activated protein kinase (MAPK); Receptor tyrosine kinase; Syndecan-1; Transcription factor