Oncotarget

Research Papers:

Platelet-derived growth factor-C promotes human melanoma aggressiveness through activation of neuropilin-1

Federica Ruffini, Lauretta Levati, Grazia Graziani, Simona Caporali, Maria Grazia Atzori, Stefania D’Atri and Pedro M. Lacal _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:66833-66848. https://doi.org/10.18632/oncotarget.18706

Metrics: HTML 1237 views  |   ?  


Abstract

Federica Ruffini1, Lauretta Levati1, Grazia Graziani2, Simona Caporali1, Maria Grazia Atzori2, Stefania D’Atri1 and Pedro M. Lacal1

1Laboratory of Molecular Oncology, “Istituto Dermopatico dell’Immacolata”-IRCCS, Rome, Italy

2Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

Correspondence to:

Pedro M. Lacal, email: p.lacal@idi.it

Keywords: PDGF-C, neuropilin-1, melanoma, metastatic phenotype, Snail

Received: January 06, 2017    Accepted: May 22, 2017    Published: June 27, 2017

ABSTRACT

Despite recent progress in advanced melanoma therapy, identification of signalling pathways involved in melanoma switch from proliferative to invasive states is still crucial to uncover new therapeutic targets for improving the outcome of metastatic disease. Neuropilin-1 (NRP-1), a co-receptor for vascular endothelial growth factor-A (VEGF-A) tyrosine kinase receptors (VEGFRs), has been suggested to play a relevant role in melanoma progression. NRP-1 can be activated by VEGF-A also in the absence of VEGFRs, triggering specific signal transduction pathways (e.g. p130Cas phosphorylation). Since melanoma cells co-expressing high levels of NRP-1 and platelet derived growth factor-C (PDGF-C) show a highly invasive behaviour and PDGF-C shares homology with VEGF-A, in this study we have investigated whether PDGF-C directly interacts with NRP-1 and promotes melanoma aggressiveness. Results demonstrate that PDGF-C specifically binds in vitro to NRP-1. In melanoma cells expressing NRP-1 but lacking PDGFRα, PDGF-C stimulates extra-cellular matrix (ECM) invasion and induces p130Cas phosphorylation. Blockade of PDGF-C function by neutralizing antibodies or reduction of its secretion by specific siRNA inhibit ECM invasion and vasculogenic mimicry. Moreover, PDGF-C silencing significantly down-modulates the expression of Snail, a transcription factor involved in tumour invasiveness that is highly expressed in NRP-1 positive melanoma cells. In conclusion, our results demonstrate for the first time a direct activation of NRP-1 by PDGF-C and strongly suggest that autocrine and/or paracrine stimulation of NRP-1 by PDGF-C might contribute to the acquisition of a metastatic phenotype by melanoma cells.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 18706