Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms

Ruffini,Federica; D'Atri,Stefania; Lacal,Pedro  M.

doi:10.3892/ijo.2013.1948

Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms

Authors:
- Federica Ruffini
- Stefania D'Atri
- Pedro M. Lacal
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Affiliations: Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, I-00167 Rome, Italy
Published online on: May 20, 2013 https://doi.org/10.3892/ijo.2013.1948
Pages: 297-306

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Abstract

The majority of human melanoma cell lines secretes vascular endothelial growth factor-A (VEGF-A) and expresses its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP‑1), a co-receptor for VEGF-A that amplifies the signalling through VEGFR-2. Since it is known that the VEGF-A/VEGFR-2 autocrine loop promotes melanoma cell invasiveness, the aim of the present study was to investigate the involvement of NPR-1 in melanoma progression. Syngeneic human melanoma cell lines expressing either VEGFR-2 or NRP-1, both or none of them, were analyzed for their in vitro ability to migrate, invade the extracellular matrix (ECM) and secrete active metalloproteinase-2 (MMP-2). The results indicate that NRP-1 cooperates with VEGFR-2 in melanoma cell migration induced by VEGF-A. Moreover, NRP-1 expression is sufficient to promote MMP-2 secretion and melanoma cell invasiveness, as demonstrated by the ability of cells expressing solely NRP-1 to spontaneously invade the ECM. This ability is specifically downregulated by anti-NRP-1 antibodies or by interfering with NRP-1 expression using an shRNA construct. Investigation of the signal transduction pathways triggered by NRP-1 in melanoma cells, indicated that NRP-1-dependent promotion of cell invasiveness involves Akt activation through its phosphorylation on T308. Overall, the results demonstrate that NRP-1 is involved in melanoma progression through VEGFR-2-dependent and -independent mechanisms and suggest NRP-1 as a target for the treatment of the metastatic disease.

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