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Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription

Lookup NU author(s): Dr Jamie Fernandez, Professor Matthew Wright

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Early in cancer development, tumour cells express vascular endothelial growth factor (VEGF), a secreted molecule that is important in all stages of angiogenesis, an essential process that provides nutrients and oxygen to the nascent tumor and thereby enhances tumor-cell survival and facilitates growth. Survivin, another protein involved in angiogenesis, is strongly expressed in most human cancers, where it promotes tumor survival by reducing apoptosis as well as favoring endothelial cell proliferation and migration. The mechanisms by which cancer cells induce VEGF expression and angiogenesis upon survivin up-regulation remain to be fully established. Since the PI3K/Akt signalling and beta-catenin-Tcf/Lef dependent transcription have been implicated in the expression of many cancer-related genes, including survivin and VEGF, we evaluated whether survivin may favor VEGF expression, release from tumor cells and induction of angiogenesis in a PI3K/Akt-beta-catenin-Tcf/Lef-dependent manner. Here, we provide evidence linking survivin expression in tumor cells to increased beta-catenin protein levels, beta-catenin-Tcf/Lef transcriptional activity and expression of several target genes of this pathway, including survivin and VEGF, which accumulates in the culture medium. Alternatively, survivin downregulation reduced beta-catenin protein levels and beta-catenin-Tcf/Lef transcriptional activity. Also, using inhibitors of PI3K and the expression of dominant negative Akt, we show that survivin acts upstream in an amplification loop to promote VEGF expression. Moreover, survivin knock-down in B16F10 murine melanoma cells diminished the number of blood vessels and reduced VEGF expression in tumors formed in C57BL/6 mice. Finally, in the chick chorioallantoid membrane assay, survivin expression in tumor cells enhanced VEGF liberation and blood vessel formation. Importantly, the presence of neutralizing anti-VEGF antibodies precluded survivin-enhanced angiogenesis in this assay. These findings provide evidence for the existance of a posititve feedback loop connecting survivin expression in tumor cells to PI3K/Akt enhanced beta-catenin-Tcf/Lef-dependent transcription followed by secretion of VEGF and angiogenesis.


Publication metadata

Author(s): Fernandez JG, Rodriguez DA, Valenzuela M, Calderon C, Urzua U, Munroe D, Rosas C, Lemus D, Diaz N, Wright MC, Leyton L, Tapia JC, Quest AFG

Publication type: Article

Publication status: Published

Journal: Molecular Cancer

Year: 2014

Volume: 13

Online publication date: 09/09/2014

Acceptance date: 27/08/2014

Date deposited: 07/11/2014

ISSN (electronic): 1476-4598

Publisher: BioMed Central Ltd.

URL: http://dx.doi.org/10.1186/1476-4598-13-209

DOI: 10.1186/1476-4598-13-209


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Funding

Funder referenceFunder name
P09-015-FIniciative Cientifica Milenio (ICM)
Anillo ACT 1111
CONICYT PhD fellowships
1090071FONDECYT
1130250FONDECYT
1110149FONDECYT
15130011CONICYT-FONDAP

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