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Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Oncogene volume 30, pages 190–200 (2011)Cite this article

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Abstract

Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-protein-coupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-γ/Rac nexus in vGPCR-mediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell–cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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Acknowledgements

We would like to thank N. Bidère (Inserm U1014, Université Paris-Sud, Hopital Paul Brousse, Villejuif, France) for helpful discussions and comments, A Schmitt (Institut Cochin, Paris, France) for technical help on electron microscopy experiments, Anne Audebourg and Brigitte Radenen (Service d'Anatomie et de Cytologie Pathologique, Hôpital Cochin, Paris, France) for technical help on histological staining, and Nina Feinberg (OPCB, NIDCR, NIH, Bethesda, MD, USA) for technical help on the initial project. This research was funded by Ligue Nationale contre le Cancer, comité de Paris and by a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme (PIRG04-GA-2008-239126). JD is supported by a post-doctoral fellowship from Fondation pour la Recherche Médicale, ALG by the PhD program from Université Paris 5 and EMGM by a post-doctoral fellowship from Association pour la Recherche sur le Cancer.

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Authors and Affiliations

  1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France

    J Dwyer, A Le Guelte, E M Galan Moya, M Sumbal, L Douguet & J Gavard

  2. Inserm, U1016, Paris, France

    J Dwyer, A Le Guelte, E M Galan Moya, M Sumbal, L Douguet & J Gavard

  3. Service d'Anatomie et de Cytologie Pathologiques, Groupe Hospitalier Cochin-Port Royal, Pavillon Tarnier, AP-HP, Faculté de Médecine, Universite Paris Descartes, Paris, France

    A Carlotti

  4. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    J S Gutkind

  5. Laboratoire de Recherche en Dermatologie, EA 1833, Faculte de Médecine, Universite Paris Descartes, Paris, France

    P A Grange & N Dupin

  6. Service de Dermatologie, Groupe Hospitalier Cochin-Port Royal Pavillon Tarnier, AP-HP, Faculte de Médecine, Université Paris Descartes, Paris, France

    N Dupin

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  1. J Dwyer
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Correspondence to J Gavard.

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Dwyer, J., Le Guelte, A., Galan Moya, E. et al. Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor. Oncogene 30, 190–200 (2011). https://doi.org/10.1038/onc.2010.411

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