title: PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omics approach.
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.
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Arcangelo
authors.affiliation: Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facchiano
authors.affiliation: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery,University of Salerno, Baronissi (SA), Italy.|Genomix4Life srl, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nassa
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stancato
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Antonini
authors.affiliation: Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Senatore
authors.affiliation: Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Cordella
authors.affiliation: Dipartimento Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tabolacci
authors.affiliation: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery,University of Salerno, Baronissi (SA), Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Salvati
authors.affiliation: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery,University of Salerno, Baronissi (SA), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Tarallo
authors.affiliation: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery,University of Salerno, Baronissi (SA), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
authors.affiliation: National Research Council Institute of Food Science, Avellino, Italy.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: Facchiano
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Facchiano
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008545:Melanoma; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: angiogenesis; cancer; melanoma; miRNA; omics