Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network.
Int J Cancer
; 143(11): 2905-2918, 2018 12 01.
Article
em En
| MEDLINE
| ID: mdl-29971782
ABSTRACT
VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF-related molecular mechanisms on breast cancer cells. VEGF-knocked-out MDA-MB-231 cells (231 VEGFKOex3 ) showed rounded morphology and shorter perimeter (1.6-fold, p < 0.0001). The 231 VEGFKOex3 cells also showed impaired cell migration (2.6-fold, p = 0.002). Bevacizumab treatment did not induce any change in morphology and mobility. Soluble neuropilin-1 overexpressing MDA-MB-231 cells (231 sNRP1 ) exhibited rounded morphology and shorter perimeter (1.3-fold, p < 0.0001). The 231 sNRP1 cells also showed impaired cell migration (1.7-fold, p = 0.003). These changes were similar to that of 231 VEGFKOex3 cells. As MDA-MB-231 cells express almost no VEGFR, these results indicate that the interaction between NRP1 and long isoform of VEGF containing a NRP-binding domain regulates the morphology and migration ability of MDA-MB-231 cells. Genome-wide gene expression profiling identified ARHGAP17 as one of the target genes in the downstream of the VEGF/NRP1 signal. We also show that VEGF/NRP1 signal controls filopodia formation of the cells by modulating Cdc42 activity via ARHGAP17. Among 1,980 breast cancer cases from a public database, the ratio of VEGF and SEMA3A in primary tumors (n = 450) of hormone-receptor-negative breast cancer is associated with ARHGAP17 expression inversely, and with disease free survival. Altogether, the bevacizumab-independent VEGF/NRP1/ARHGAP17/Cdc42 regulatory network plays important roles in malignant behavior of breast cancer.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pseudópodes
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Neoplasias da Mama
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Movimento Celular
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Isoformas de Proteínas
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Proteínas Ativadoras de GTPase
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Neuropilina-1
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Fator A de Crescimento do Endotélio Vascular
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article