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The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo

Oncogene volume 27, pages 3662–3672 (2008)Cite this article

Abstract

Vascularization is an important step in tumour growth. Although a variety of molecules, for example, VEGF, ETS-1 or nestin have been implicated in tumour angiogenesis, the molecular mechanisms of vessel formation are not fully characterized. We showed that the Wilms' tumour suppressor WT1 activates nestin during development. Here we tested whether WT1 might also be involved in tumour angiogenesis. Endothelial WT1 expression was detected in 95% of 113 tumours of different origin. To analyse the function of WT1 in endothelial cells, we used an RNAi approach in vitro and showed that inhibition of WT1 reduces cell proliferation, migration and endothelial tube formation. On a molecular level, WT1 silencing diminished expression of the ETS-1 transcription factor. WT1 and ETS-1 shared an overlapping expression in tumour endothelia. The ETS-1 promoter was stimulated approximately 10-fold by transient co-transfection of a WT1 expression construct and WT1 bound to the ETS-1 promoter in chromatin immunoprecipitation and electrophoretic mobility shift assays. Deletion of the identified WT1-binding site abolished stimulation of the ETS-1 promoter by WT1. These findings suggest that transcriptional activation of ETS-1 by the Wilms' tumour suppressor WT1 is a crucial step in tumour vascularization via regulation of endothelial cell proliferation and migration.

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Acknowledgements

The WT1 expression constructs, the ETS-1 promoter construct and the VEGFR2 promoter construct were gifts from D Haber, D Watson and C Patterson, respectively. The human umbilical endothelial cells (HUVECs) were a gift from E Van Obberghen-Schilling. J Haudebourg helped with the tumour sections. KD Wagner and N Wagner are recipients of fellowships from INSERM and EMBO (KDW.), the Deutsche Forschungsgemeinschaft (DFG), INSERM and Fondation de France (NW). This study was supported in part by grants from the Association pour le Recherche contre le Cancer (no. 5198), EC (no. LSHG-CT-2004-005085) and INSERM AVENIR.

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Authors and Affiliations

  1. INSERM U907, Nice, France

    N Wagner & K-D Wagner

  2. Université de Nice-Sophia Antipolis, Nice, France

    N Wagner, J F Michiels, A Schedl & K-D Wagner

  3. Department of Pathology, Université de Nice-Sophia Antipolis, Nice, France

    J F Michiels

  4. INSERM U636, Nice, France

    A Schedl

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Correspondence to K-D Wagner.

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Wagner, N., Michiels, J., Schedl, A. et al. The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo. Oncogene 27, 3662–3672 (2008). https://doi.org/10.1038/sj.onc.1211044

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