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Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network
Author(s) -
Kiso Marina,
Tanaka Sunao,
Saji Shigehira,
Toi Masakazu,
Sato Fumiaki
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31645
Subject(s) - neuropilin 1 , filopodia , cdc42 , cancer research , angiogenesis , cell migration , cancer cell , biology , microbiology and biotechnology , cell , vascular endothelial growth factor , cancer , medicine , signal transduction , vegf receptors , actin , genetics
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.