Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells.
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.
Friand
Veronique
V
INSERM U698, Université Paris 13, Bobigny, France.
Haddad
Oualid
O
Papy-Garcia
Dulce
D
Hlawaty
Hanna
H
Vassy
Roger
R
Hamma-Kourbali
Yamina
Y
Perret
Gerard-Yves
GY
Courty
Jose
J
Baleux
Françoise
F
Oudar
Olivier
O
Gattegno
Liliane
L
Sutton
Angela
A
Charnaux
Nathalie
N
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
D054377:Chemokine CXCL12; D005966:Glucuronidase; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D034741:RNA, Small Interfering; D000099175:Heparanase; C515255:CXCL12 protein, human