PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omics approach.

// Daniela D’Arcangelo 1 , Francesco Facchiano 2 , Giovanni Nassa 3, 4 , Andrea Stancato 1 , Annalisa Antonini 1 , Stefania Rossi 2 , Cinzia Senatore 2 , Martina Cordella 2 , Claudio Tabolacci 2 , Annamaria Salvati 3 , Roberta Tarallo 3 , Alessandro Weisz 3 , Angelo M. Facchiano 5 , Antonio Facchiano 1 1 Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy 2 Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita, Rome, Italy 3 Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery,University of Salerno, Baronissi (SA), Italy 4 Genomix4Life srl, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy 5 National Research Council Institute of Food Science, Avellino, Italy Correspondence to: Daniela D’Arcangelo, email: d.darcangelo@idi.it Antonio Facchiano, email: a.facchiano@idi.it Keywords: cancer, omics, angiogenesis, miRNA, melanoma Received: April 15, 2016     Accepted: September 25, 2016     Published: October 13, 2016 ABSTRACT Melanoma is the most aggressive skin-cancer, showing high mortality at advanced stages. Platelet Derived Growth Factor Receptor-alpha (PDGFR-alpha) potently inhibits melanoma- and endothelium-proliferation and its expression is significantly reduced in melanoma-biopsies, suggesting that melanoma progression eliminates cells expressing PDGFR-alpha. In the present study transient overexpression of PDGFR-alpha in endothelial (HUVEC) and melanoma (SKMel-28, A375, Preyer) human-cells shows strong anti-proliferative effects, with profound transcriptome and miRNome deregulation. PDGFR-alpha overexpression strongly affects expression of 82 genes in HUVEC (41 up-, 41 down-regulated), and 52 genes in SKMel-28 (43 up-, 9 down-regulated). CXCL10/IP-10 transcript showed up to 20 fold-increase, with similar changes detectable at the protein level. miRNA expression profiling in cells overexpressing PDGFR-alpha identified 14 miRNAs up- and 40 down-regulated, with miR-503 being the most down-regulated (6.4 fold-reduction). miR-503, miR-630 and miR-424 deregulation was confirmed by qRT-PCR. Interestingly, the most upregulated transcript (i.e., CXCL10/IP-10) was a validated miR-503 target and CXCL10/IP-10 neutralization significantly reverted the anti-proliferative action of PDGFR-alpha, and PDGFR-alpha inhibition by Dasatinb totally reverted the CXCL10/IP10 induction, further supporting a functional interplay of these factors. Finally, integration of transcriptomics and miRNomics data highlighted several pathways affected by PDGFR-alpha. This study demonstrates for the first time that PDGFR-alpha strongly inhibits endothelial and melanoma cells proliferation in a CXCL10/IP-10 dependent way, via miR-503 down-regulation.