Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis

Tumor angiogenesis is mainly mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic factor produced by cancer cells and active on the endothelium through the VEGF receptor 2 (VEGFR-2). Here we identify a G-rich sequence within the proximal promoter region of vegfr-2, able to form an...

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Published in:Nucleic acids research 2014-03, Vol.42 (5), p.2945-2957
Main Authors: Salvati, Erica, Zizza, Pasquale, Rizzo, Angela, Iachettini, Sara, Cingolani, Chiara, D'Angelo, Carmen, Porru, Manuela, Randazzo, Antonio, Pagano, Bruno, Novellino, Ettore, Pisanu, Maria Elena, Stoppacciaro, Antonella, Spinella, Francesca, Bagnato, Anna, Gilson, Eric, Leonetti, Carlo, Biroccio, Annamaria
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cells, Cultured
G-Quadruplexes
Gene Regulation, Chromatin and Epigenetics
Human Umbilical Vein Endothelial Cells - physiology
Humans
Ligands
Mice
Mice, Inbred C57BL
Mice, Nude
Neoplasms - blood supply
Neovascularization, Pathologic
Neovascularization, Physiologic
Promoter Regions, Genetic
Vascular Endothelial Growth Factor Receptor-2 - genetics
Vascular Endothelial Growth Factor Receptor-2 - metabolism
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Summary:Tumor angiogenesis is mainly mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic factor produced by cancer cells and active on the endothelium through the VEGF receptor 2 (VEGFR-2). Here we identify a G-rich sequence within the proximal promoter region of vegfr-2, able to form an antiparallel G-quadruplex (G4) structure. This G4 structure can be efficiently stabilized by small molecules with the consequent inhibition of vegfr-2 expression. Functionally, the G4-mediated reduction of VEGFR-2 protein causes a switching off of signaling components that, converging on actin cytoskeleton, regulate the cellular events leading to endothelial cell proliferation, migration and differentiation. As a result of endothelial cell function impairment, angiogenic process is strongly inhibited by G4 ligands both in vitro and in vivo. Interestingly, the G4-mediated antiangiogenic effect seems to recapitulate that observed by using a specific interference RNA against vegfr-2, and it is strongly antagonized by overexpressing the vegfr-2 gene. In conclusion, we describe the evidence for the existence of G4 in the promoter of vegfr-2, whose expression and function can be markedly inhibited by G4 ligands, thereby revealing a new, and so far undescribed, way to block VEGFR-2 as target for anticancer therapy.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkt1289