title: Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion.
abstract: In addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. The aim of this study was to determine whether the chemokine stromal cell-derived factor 1 (SDF-1) induces the growth, migration, and invasion of human hepatoma cells. We show that SDF-1 G protein-coupled receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), and SDF-1 mRNA are expressed in human hepatoma Huh7 cells, which secrete and bind SDF-1. This binding depends on CXCR4 and glycosaminoglycans. SDF-1 associates with CXCR4, and syndecan-4 (SDC-4), a heparan sulfate proteoglycan at the plasma membrane of Huh7 cells, induces the growth of Huh7 cells by promoting their entry into the cell cycle, and inhibits the tumor necrosis factor-alpha-mediated apoptosis of the cells. SDF-1 also reorganizes Huh7 cytoskeleton and induces tyrosine phosphorylation of focal adhesion kinase. Finally, SDF-1 activates matrix metalloproteinase-9, resulting in increased migration and invasion of Huh7 cells. These biological effects of SDF-1 were strongly inhibited by the CXCR4 antagonist AMD3100, by a glycosaminoglycan, heparin, as well as by beta-D-xyloside treatment of the cells, or by c-jun NH(2)-terminal kinase/stress-activated protein kinase inhibitor. Therefore, the CXCR4, glycosaminoglycans, and the mitogen-activated protein kinase signaling pathways are involved in these events. The fact that reducing SDC-4 expression by RNA interference decreased SDF-1-induced Huh7 hepatoma cell migration and invasion strongly indicates that SDC-4 may be an auxiliary receptor for SDF-1. Finally, the fact that CXCR4 is expressed in hepatocellular carcinoma cells from liver biopsies indicates that the in vitro results reported here could be extended to in vivo conditions.
authors.affiliation: UPRES 3410, Université Paris XIII, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton
authors.forename: Veronique
authors.initials: V
authors.lastname: Friand
authors.forename: Severine
authors.initials: S
authors.lastname: Brulé-Donneger
authors.forename: Thomas
authors.initials: T
authors.lastname: Chaigneau
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.forename: Odile
authors.initials: O
authors.lastname: Sainte-Catherine
authors.forename: Aurelie
authors.initials: A
authors.lastname: Poiré
authors.forename: Line
authors.initials: L
authors.lastname: Saffar
authors.forename: Michel
authors.initials: M
authors.lastname: Kraemer
authors.forename: Jany
authors.initials: J
authors.lastname: Vassy
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Salzmann
authors.forename: Liliane
authors.initials: L
authors.lastname: Gattegno
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006025:Glycosaminoglycans / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D053668:Syndecan-1 / Q000378:metabolism; D053669:Syndecan-2 / Q000378:metabolism; D053671:Syndecan-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D006025:Glycosaminoglycans; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D053668:Syndecan-1; D053671:Syndecan-4; D053669:Syndecan-2; D014443:Tyrosine; D020928:Mitogen-Activated Protein Kinases