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Updated: Mar 13, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omics approach
Daniela D'Arcangelo1, Francesco Facchiano2, Giovanni Nassa3,4
1Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Fondazione Luigi Maria Monti, Rome, Italy.
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.
Insights
Platelet Derived Growth Factor Receptor-alpha (PDGFR-alpha) inhibits melanoma and endothelial cell proliferation. This study reveals PDGFR-alpha acts via CXCL10/IP-10 and miR-503, offering new therapeutic insights for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Melanoma is an aggressive skin cancer with high mortality.
- Reduced Platelet Derived Growth Factor Receptor-alpha (PDGFR-alpha) expression correlates with melanoma progression.
- PDGFR-alpha's role in inhibiting proliferation suggests a tumor-suppressive function.
Purpose of the Study:
- To investigate the anti-proliferative effects of PDGFR-alpha in melanoma and endothelial cells.
- To elucidate the molecular mechanisms, including transcriptome and miRNome changes, underlying PDGFR-alpha's action.
- To explore the functional interplay between PDGFR-alpha, CXCL10/IP-10, and miR-503.
Main Methods:
- Transient overexpression of PDGFR-alpha in human endothelial (HUVEC) and melanoma (SKMel-28, A375, Preyer) cells.
- Transcriptome and miRNome profiling (RNA-Seq, miRNA-Seq).
- Quantitative real-time PCR (qRT-PCR), protein level analysis, and functional neutralization assays.
Main Results:
- PDGFR-alpha overexpression significantly inhibited proliferation and altered gene expression in both cell types.
- CXCL10/IP-10 was highly upregulated, and miR-503 was significantly downregulated upon PDGFR-alpha overexpression.
- CXCL10/IP-10 neutralization reversed PDGFR-alpha's anti-proliferative effect, and PDGFR-alpha inhibition by Dasatinib reversed CXCL10/IP-10 induction.
Conclusions:
- PDGFR-alpha inhibits endothelial and melanoma cell proliferation through a mechanism involving CXCL10/IP-10 and miR-503 downregulation.
- This study establishes a novel functional link between PDGFR-alpha, CXCL10/IP-10, and miR-503 in melanoma.
- Findings provide potential therapeutic targets for melanoma treatment.
