Abstract
Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI: http://dx.doi.org/10.7554/eLife.01460.001.
Keywords:
BRAF; NRAS; melanoma; miRNA.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Disease Progression
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Melanoma / genetics
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Melanoma / metabolism*
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Melanoma / secondary
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Mutation
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Signal Transduction*
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism*
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Skin Neoplasms / pathology
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Time Factors
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Transfection
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Tumor Burden
Substances
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MIRN146 microRNA, human
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Membrane Proteins
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MicroRNAs
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Nerve Tissue Proteins
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NUMB protein, human
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Receptors, Notch
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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GTP Phosphohydrolases
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NRAS protein, human