Integrated genomics identifies MiR-181/TFAM pathway as a critical driver of drug resistance in melanoma

Anna Barbato, Antonella Iuliano, Mariagrazia Volpe, Romina D’alterio, Simona Brillante, Filomena Massa, Rossella De Cegli, Sabrina Carrella, Massimiliano Salati, Annapina Russo, Giulia Russo, Sara Riccardo, Davide Cacchiarelli, Mariaelena Capone, Gabriele Madonna, Paolo A. Ascierto, Brunella Franco, Alessia Indrieri, Pietro Carotenuto

Research output: Contribution to journalArticlepeer-review

Abstract

MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and-181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensi-tive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and-181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and-181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.

Original languageEnglish
Article number1801
Pages (from-to)1-27
Number of pages27
JournalInternational Journal of Molecular Sciences
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 2 2021

Keywords

  • Biomarkers
  • BRAF inhibitors
  • Cancer resistance
  • Dabrafenib
  • Melanoma
  • MicroRNA
  • MiR-181
  • Mitochondria
  • Target therapy
  • TFAM

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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