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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
miR-579-3p controls melanoma progression and resistance to target therapy
Luigi Fattore1, Rita Mancini2, Mario Acunzo3
1Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
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.
Insights
Low miR-579-3p expression predicts poor survival in melanoma patients. This microRNA targets BRAF and MDM2, acting as an oncosuppressor and potentially overcoming drug resistance to BRAF/MEK inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Targeted therapy combining BRAF and MEK inhibitors is standard for BRAF-mutant melanoma.
- Drug resistance remains a significant challenge, limiting long-term patient survival.
- MicroRNAs (miRNAs) are emerging as critical regulators in cancer development and drug resistance.
Purpose of the Study:
- To investigate the role of miR-579-3p in melanoma progression and resistance to BRAF/MEK inhibitors.
- To identify the molecular targets and mechanisms through which miR-579-3p exerts its function.
Main Methods:
- Analysis of miR-579-3p expression in melanoma patient samples and cell lines.
- Correlation of miR-579-3p levels with patient survival and drug resistance status.
- Luciferase reporter assays and Western blotting to confirm target interactions (BRAF, MDM2).
- Ectopic expression of miR-579-3p in melanoma cells to assess its impact on drug resistance.
Main Results:
- Low miR-579-3p expression is a negative prognostic factor for melanoma patient survival.
- miR-579-3p levels decrease progressively from nevi to advanced melanoma and drug-resistant cell lines.
- miR-579-3p directly targets the 3' untranslated region (3'UTR) of BRAF and MDM2 oncogenes.
- Ectopic expression of miR-579-3p inhibits the development of drug resistance in melanoma cells.
- A significant downregulation of miR-579-3p was observed in patients who developed resistance to targeted therapy.
Conclusions:
- miR-579-3p functions as a tumor suppressor in melanoma.
- Downregulation of miR-579-3p is implicated in the development of resistance to BRAF/MEK inhibitors.
- miR-579-3p represents a potential biomarker for prognosis and a therapeutic target for overcoming drug resistance in melanoma.
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