title: Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells.
abstract: We have recently reported that the CXC-chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 induces proliferation, migration, and invasion of the Huh7 human hepatoma cells through its G-protein-coupled receptor CXCR4 and that glycosaminoglycans (GAGs) are involved in these events. Here, we demonstrate by surface plasmon resonance that the chemokine binds to GAG mimetics obtained by grafting carboxylate, sulfate or acetate groups onto a dextran backbone. We also demonstrate that chemically modified dextrans inhibit SDF-1/CXCL12-mediated in vitro chemotaxis and anchorage-independent cell growth in a dose-dependent manner. The binding of GAG mimetics to the chemokine and their effects in modulating the SDF-1/CXCL12 biological activities are mainly related to the presence of sulfate groups. Furthermore, the mRNA expression of enzymes involved in heparan sulfate biosynthesis, such as exostosin-1 and -2 or N-deacetylase N-sulfotransferases remained unchanged, but heparanase mRNA and protein expressions in Huh7 cells were decreased upon GAG mimetic treatment. Moreover, decreasing heparanase-1 mRNA levels by RNA interference significantly reduced SDF-1/CXCL12-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Therefore, we suggest that GAG mimetic effects on SDF-1/CXCL12-mediated hepatoma cell chemotaxis may rely on decreased heparanase expression, which impairs SDF-1/CXCL12's signaling. Altogether, these data suggest that GAG mimetics may compete with cellular heparan sulfate chains for the binding to SDF-1/CXCL12 and may affect heparanase expression, leading to reduced SDF-1/CXCL12 mediated in vitro chemotaxis and growth of hepatoma cells.
authors.affiliation: INSERM U698, Université Paris 13, Bobigny, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Friand
authors.forename: Oualid
authors.initials: O
authors.lastname: Haddad
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
authors.forename: Hanna
authors.initials: H
authors.lastname: Hlawaty
authors.forename: Roger
authors.initials: R
authors.lastname: Vassy
authors.forename: Yamina
authors.initials: Y
authors.lastname: Hamma-Kourbali
authors.forename: Gerard-Yves
authors.initials: GY
authors.lastname: Perret
authors.forename: Jose
authors.initials: J
authors.lastname: Courty
authors.forename: Françoise
authors.initials: F
authors.lastname: Baleux
authors.forename: Olivier
authors.initials: O
authors.lastname: Oudar
authors.forename: Liliane
authors.initials: L
authors.lastname: Gattegno
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006025:Glycosaminoglycans / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099175:Heparanase
chemical_list: D054377:Chemokine CXCL12; D005966:Glucuronidase; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D034741:RNA, Small Interfering; D000099175:Heparanase; C515255:CXCL12 protein, human