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.

• Authors: Federica Ruffini, Stefania D'Atri, Pedro M Lacal
• Journal: International journal of oncology (Int J Oncol) Vol. 43 Issue 1 Pg. 297-306 (Jul 2013) ISSN: 1791-2423 [Electronic] Greece
• PMID: 23685409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vascular Endothelial Growth Factor A
• Neuropilin-1
• Vascular Endothelial Growth Factor Receptor-2
• Matrix Metalloproteinase 2

Topics

• Cell Line, Tumor
• Extracellular Matrix (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Melanoma (genetics, pathology)
• Neoplasm Invasiveness (genetics, pathology)
• Neoplasm Metastasis (genetics, pathology)
• Neuropilin-1 (genetics, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)