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miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth

Author

Listed:
  • Marija Mihailovich

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy)

  • Michael Bremang

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy)

  • Valeria Spadotto

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy)

  • Daniele Musiani

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy)

  • Elena Vitale

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy)

  • Gabriele Varano

    (Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation
    Present address: Department of Oncological Sciences Icahn School of Medicine at Mount Sinai One Gustave L. Levy, Box 1075, New York, New York 10029, USA)

  • Federico Zambelli

    (Milan University)

  • Francesco M. Mancuso

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
    Present address: Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain)

  • David A. Cairns

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
    Present address: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK)

  • Giulio Pavesi

    (Milan University)

  • Stefano Casola

    (Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation)

  • Tiziana Bonaldi

    (European Institute of Oncology, Via Adamello 16, Milan 20139, Italy)

Abstract

The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3′ untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3′ UTR shortening at different stages of tumorigenesis.

Suggested Citation

  • Marija Mihailovich & Michael Bremang & Valeria Spadotto & Daniele Musiani & Elena Vitale & Gabriele Varano & Federico Zambelli & Francesco M. Mancuso & David A. Cairns & Giulio Pavesi & Stefano Casola, 2015. "miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth," Nature Communications, Nature, vol. 6(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9725
    DOI: 10.1038/ncomms9725
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