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Elife. 2014 Feb 18;3:e01460. doi: 10.7554/eLife.01460.

miR-146a promotes the initiation and progression of melanoma by activating Notch signaling.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, United States.

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

PMID:
24550252
PMCID:
PMC3927633
DOI:
10.7554/eLife.01460
[Indexed for MEDLINE]
Free PMC Article

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