期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 34, 页码 E5005-E5013出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1607753113
关键词
miRNA; melanoma; targeted therapy; drug resistance
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Fondazione Melanoma ONLUS (Organizzazione non Lucrativa di Utilita Sociale)
- AIRC Grants [IG15216, IG17009]
- AIRC/FIRC (Fondazione Italiana per la Ricerca sul Cancro) fellowship
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 lowexpression ofmiR-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.
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