Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and γ-adducin

  • Authors:
    • S. Matou-Nasri
    • J. Gaffney
    • S. Kumar
    • M. Slevin
  • View Affiliations

  • Published online on: October 1, 2009     https://doi.org/10.3892/ijo_00000389
  • Pages: 761-773
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Abstract

We used short-interfering RNA (siRNA) to knockdown the hyaluronan (HA) receptors CD44 and the receptor for hyaluronan-mediated motility (RHAMM) in vascular endothelial cells to investigate their role in angiogenesis. We showed that CD44 and RHAMM single knockdown inhibited low molecular weight hyaluronan (o-HA)-induced endothelial cell tube formation in Matrigel, but no change in the control, epidermal growth factor-induced tube formation was observed. Using a Kinexus phosphoprotein array and confirmational Western blotting we were able to show a differential effect on HA-induced protein expression after CD44 and RHAMM knockdown. CD44 knockdown abolished o-HA-induced membrane phospho-protein kinase C-α (PKC-α) and down-stream phospho-γ-adducin expression. Using the PKC inhibitor Go6976, we demonstrated the involvement of PKC-α and γ-adducin in o-HA-induced tube formation, whilst o-HA-induced enzymatic activity of MMP9 was also reduced. This suggests that endothelial tube formation involves activation of MMP9 via PKC-α. Furthermore, the involvement of γ-adducin in o-HA-induced F-actin cytoskeleton rearrangement was CD44-dependent and the reduction of CD44 expression lead to a change in endothelial cell morphology. Both RHAMM and CD44 knockdown completely inhibited o-HA-induced Cdc2 (Cdk1) phosphorylation suggesting a possible involvement in cell cycle control. Although CD44 and RHAMM are both involved in o-HA-induced endothelial tube formation in Matrigel, they mediate distinct angiogenic signalling pathway and for the first time we demonstrated the specific involvement of γ-adducin in CD44/o-HA-induced endothelial tube formation. The data presented here extend our understanding of key stages of the processes of o-HA-induced angiogenesis which may have relevance to tumour progression.

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October 2009
Volume 35 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Matou-Nasri S, Gaffney J, Kumar S and Slevin M: Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and γ-adducin. Int J Oncol 35: 761-773, 2009
APA
Matou-Nasri, S., Gaffney, J., Kumar, S., & Slevin, M. (2009). Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and γ-adducin. International Journal of Oncology, 35, 761-773. https://doi.org/10.3892/ijo_00000389
MLA
Matou-Nasri, S., Gaffney, J., Kumar, S., Slevin, M."Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and γ-adducin". International Journal of Oncology 35.4 (2009): 761-773.
Chicago
Matou-Nasri, S., Gaffney, J., Kumar, S., Slevin, M."Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and γ-adducin". International Journal of Oncology 35, no. 4 (2009): 761-773. https://doi.org/10.3892/ijo_00000389