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

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)297-306
Number of pages10
JournalInternational Journal of Oncology
Volume43
Issue number1
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Neuropilin-1
Vascular Endothelial Growth Factor Receptor-2
Melanoma
Vascular Endothelial Growth Factor A
Extracellular Matrix
Vascular Endothelial Growth Factor Receptor-1
Cell Line
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Small Interfering RNA
Cell Movement
Signal Transduction

Keywords

  • Cell invasiveness
  • Melanoma
  • Metalloproteinase-2
  • Neuropilin-1
  • VEGFR-2

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms",
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.",
keywords = "Cell invasiveness, Melanoma, Metalloproteinase-2, Neuropilin-1, VEGFR-2",
author = "Federica Ruffini and Stefania D'Atri and Lacal, {Pedro M.}",
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T1 - Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms

AU - Ruffini, Federica

AU - D'Atri, Stefania

AU - Lacal, Pedro M.

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N2 - 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.

AB - 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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