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

Academic Article

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.
  • Published In

  • eLife  Journal
  • Keywords

  • BRAF, NRAS, melanoma, miRNA, Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Disease Progression, GTP Phosphohydrolases, Gene Expression Regulation, Neoplastic, Humans, Melanoma, Membrane Proteins, Mice, Nude, MicroRNAs, Mutation, Nerve Tissue Proteins, Proto-Oncogene Proteins B-raf, Receptors, Notch, Signal Transduction, Skin Neoplasms, Time Factors, Transfection, Tumor Burden
  • Digital Object Identifier (doi)

    Author List

  • Forloni M; Dogra SK; Dong Y; Conte D; Ou J; Zhu LJ; Deng A; Mahalingam M; Green MR; Wajapeyee N
  • Start Page

  • e01460
  • Volume

  • 3