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

Erica Salvati, Pasquale Zizza, Angela Rizzo, Sara Iachettini, Chiara Cingolani, Carmen D'angelo, Manuela Porru, Antonio Randazzo, Bruno Pagano, Ettore Novellino, Maria Elena Pisanu, Antonella Stoppacciaro, Francesca Spinella, Anna Bagnato, Eric Gilson, Carlo Leonetti, Annamaria Biroccio

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2945-2957
Number of pages13
JournalNucleic Acids Research
Volume42
Issue number5
DOIs
Publication statusPublished - 2014

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G-Quadruplexes
Vascular Endothelial Growth Factor Receptor
Endothelial Cells
Ligands
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Inducing Agents
RNA Interference
Actin Cytoskeleton
Genetic Promoter Regions
Vascular Endothelial Growth Factor A
Endothelium
Cell Movement
Cell Differentiation
Neoplasms
Cell Proliferation
Genes
Proteins
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Genetics

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

In: Nucleic Acids Research, Vol. 42, No. 5, 2014, p. 2945-2957.

Research output: Contribution to journalArticle

Salvati, E, Zizza, P, Rizzo, A, Iachettini, S, Cingolani, C, D'angelo, C, Porru, M, Randazzo, A, Pagano, B, Novellino, E, Pisanu, ME, Stoppacciaro, A, Spinella, F, Bagnato, A, Gilson, E, Leonetti, C & Biroccio, A 2014, 'Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis', Nucleic Acids Research, vol. 42, no. 5, pp. 2945-2957. https://doi.org/10.1093/nar/gkt1289
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. / Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 5. pp. 2945-2957.
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AU - Salvati, Erica

AU - Zizza, Pasquale

AU - Rizzo, Angela

AU - Iachettini, Sara

AU - Cingolani, Chiara

AU - D'angelo, Carmen

AU - Porru, Manuela

AU - Randazzo, Antonio

AU - Pagano, Bruno

AU - Novellino, Ettore

AU - Pisanu, Maria Elena

AU - Stoppacciaro, Antonella

AU - Spinella, Francesca

AU - Bagnato, Anna

AU - Gilson, Eric

AU - Leonetti, Carlo

AU - Biroccio, Annamaria

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