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Glycobiology Advance Access originally published online on August 28, 2009
Glycobiology 2009 19(12):1511-1524; doi:10.1093/glycob/cwp130
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells

Veronique Friand3, Oualid Haddad3, Dulce Papy-Garcia4, Hanna Hlawaty3, Roger Vassy5, Yamina Hamma-Kourbali4, Gerard-Yves Perret5, Jose Courty4, Françoise Baleux6, Olivier Oudar3, Liliane Gattegno3,7, Angela Sutton2,3,7 and Nathalie Charnaux1,2,3,7

3 INSERM U698, Université Paris 13, Bobigny
4 UMR CNRS 7149, Université Paris EST-Creteil
5 UMR CNRS 7033, Université Paris 13, Bobigny
6 Institut Pasteur, Unité de Chimie des Biomoléules CNRS URA2128
7 Laboratoire de Biochimie, Hôpital Jean Verdier AP-HP, Bondy, France

1 To whom correspondence should be addressed: Tel: +33-1-48-02-65-13; Fax: +33-1-48-02-65-03; e-mail: nathalie.charnaux{at}jvr.aphp.fr

Received on December 16, 2008; revised on July 27, 2009; accepted on August 18, 2009

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.

Key words: chemokine / glycosaminoglycan / glycosaminoglycan mimetics / hepatocellular carcinoma / SDF-1 / CXCL12

2 Contributed equally to the work.


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