microRNA-378a-5p iS a novel positive regulator of melanoma progression

Maria Grazia Tupone, Simona D’Aguanno, Marta Di Martile, Elisabetta Valentini, Marianna Desideri, Daniela Trisciuoglio, Sara Donzelli, Andrea Sacconi, Simonetta Buglioni, Cristiana Ercolani, Alessio Biagioni, Gabriella Fibbi, Luigi Fattore, Rita Mancini, Gennaro Ciliberto, Giovanni Blandino, Donatella Del Bufalo

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Abstract

Evaluating the expression levels of miR-378a-5p both in a large melanoma patient cohort from The Cancer Genome Atlas database and in melanoma patients from our Institute, we found that miR-378a-5p is upregulated in metastatic melanoma specimens. miR-378a-5p expression was also increased in melanoma cells resistant to target therapy, and decreased in response to drug treatment. We also demonstrated that overexpression of miR-378a-5p enhances in vitro cell invasion and migration, and facilitates the ability of melanoma cells to form de novo vasculogenic structures. While performing downstream targeting studies, we confirmed the ability of miR-378a-5p to modulate the expression of known target genes, such as SUFU, FUS-1, and KLF9. Luciferase-3′UTR experiments also identified STAMBP and HOXD10 as new miR-378a-5p target genes. MMP2 and uPAR, two HOXD10 target genes, were positively regulated by miR-378a-5p. Genetic and pharmacologic approaches inhibiting uPAR expression and activity evidenced that the in vitro tumor-promoting functions of miR-378a-5p, were in part mediated by uPAR. Of note miR-378a-5p was also able to increase VEGF, as well as in vitro and in vivo angiogenesis. Finally, genetic and pharmacologic modulation of Bcl-2 evidenced Bcl-2 ability to regulate miR-378a-5p expression. In conclusion, to the best of our knowledge, this is the first study demonstrating that miR-378a-5p acts as an oncogenic microRNA in melanoma.

Original languageEnglish
Article number22
JournalOncogenesis
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 1 2020

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Tupone, M. G., D’Aguanno, S., Di Martile, M., Valentini, E., Desideri, M., Trisciuoglio, D., Donzelli, S., Sacconi, A., Buglioni, S., Ercolani, C., Biagioni, A., Fibbi, G., Fattore, L., Mancini, R., Ciliberto, G., Blandino, G., & Del Bufalo, D. (2020). microRNA-378a-5p iS a novel positive regulator of melanoma progression. Oncogenesis, 9(2), [22]. https://doi.org/10.1038/s41389-020-0203-6