PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omics approach
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Daniela D’Arcangelo1, Francesco Facchiano2, Giovanni Nassa3,4, Andrea Stancato1, Annalisa Antonini1, Stefania Rossi2, Cinzia Senatore2, Martina Cordella2, Claudio Tabolacci2, Annamaria Salvati3, Roberta Tarallo3, Alessandro Weisz3, Angelo M. Facchiano5, Antonio Facchiano1
1Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy
2Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy
3Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery,University of Salerno, Baronissi (SA), Italy
4Genomix4Life srl, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy
5National Research Council Institute of Food Science, Avellino, Italy
Daniela D’Arcangelo, email: [email protected]
Antonio Facchiano, email: [email protected]
Keywords: cancer, omics, angiogenesis, miRNA, melanoma
Received: April 15, 2016 Accepted: September 25, 2016 Published: October 13, 2016
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.
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