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

Daniela Agnese D'Arcangelo, Francesco Facchiano, Giovanni Nassa, Andrea Stancato, Annalisa Antonini, Stefania Rossi, Cinzia Senatore, Martina Cordella, Claudio Tabolacci, Annamaria Salvati, Roberta Tarallo, Alessandro Weisz, Angelo M. Facchiano, Antonio Facchiano

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)77257-77275
Number of pages19
JournalOncotarget
Volume7
Issue number47
Publication statusPublished - 2016

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Keywords

  • Angiogenesis
  • Cancer
  • Melanoma
  • MiRNA
  • Omics

ASJC Scopus subject areas

  • Oncology

Cite this

D'Arcangelo, D. A., Facchiano, F., Nassa, G., Stancato, A., Antonini, A., Rossi, S., Senatore, C., Cordella, M., Tabolacci, C., Salvati, A., Tarallo, R., Weisz, A., Facchiano, A. M., & Facchiano, A. (2016). PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: A multi-omics approach. Oncotarget, 7(47), 77257-77275.