miR-579-3p controls melanoma progression and resistance to target therapy

Luigi Fattore, Rita Mancini, Mario Acunzo, Giulia Romano, Alessandro Laganà, Maria Elena Pisanu, Debora Malpicci, Gabriele Madonna, Domenico Mallardo, Mariaelena Capone, Franco Fulcinitif, Luca Mazzucchelli, Gerardo Botti, Carlo M. Croce, Paolo Antonio Ascierto, Gennaro Ciliberto

Research output: Contribution to journalArticle

Abstract

Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3′UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.

Original languageEnglish
Pages (from-to)E5005-E5013
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number34
DOIs
Publication statusPublished - Aug 23 2016

Keywords

  • Drug resistance
  • Melanoma
  • miRNA
  • Targeted therapy

ASJC Scopus subject areas

  • General

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  • Cite this

    Fattore, L., Mancini, R., Acunzo, M., Romano, G., Laganà, A., Pisanu, M. E., Malpicci, D., Madonna, G., Mallardo, D., Capone, M., Fulcinitif, F., Mazzucchelli, L., Botti, G., Croce, C. M., Ascierto, P. A., & Ciliberto, G. (2016). miR-579-3p controls melanoma progression and resistance to target therapy. Proceedings of the National Academy of Sciences of the United States of America, 113(34), E5005-E5013. https://doi.org/10.1073/pnas.1607753113