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  • The EMBO Journal (2007) 26, 3699 - 3708
  • doi:10.1038/sj.emboj.7601790

Published online: 12 July 2007

Regulation of the p27Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation

Carlos le Sage1,a, Remco Nagel1,a, David A Egan2, Mariette Schrier1, Elly Mesman1, Annunziato Mangiola3, Corrado Anile3, Giulio Maira3, Neri Mercatelli4, Silvia Anna Ciafrè4, Maria Giulia Farace4 and Reuven Agami1

  1. Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  2. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  3. Department of Neurosurgery, Catholic University of the Sacred Heart, Rome, Italy
  4. Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy

Correspondence to:

Reuven Agami, Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands. Tel.: +31 20 512 2079; Fax: +31 20 512 2029; E-mail: r.agami@nki.nl

aThese authors contributed equally to this work

Received 6 May 2007; Accepted 14 June 2007

MicroRNAs (miRNAs) are potent post-transcriptional regulators of protein coding genes. Patterns of misexpression of miRNAs in cancer suggest key functions of miRNAs in tumorigenesis. However, current bioinformatics tools do not entirely support the identification and characterization of the mode of action of such miRNAs. Here, we used a novel functional genetic approach and identified miR-221 and miR-222 (miR-221&222) as potent regulators of p27Kip1, a cell cycle inhibitor and tumor suppressor. Using miRNA inhibitors, we demonstrate that certain cancer cell lines require high activity of miR-221&222 to maintain low p27Kip1 levels and continuous proliferation. Interestingly, high levels of miR-221&222 appear in glioblastomas and correlate with low levels of p27Kip1 protein. Thus, deregulated expression of miR-221&222 promotes cancerous growth by inhibiting the expression of p27Kip1.

  • Keywords:

    • cancer,
    • genetic screen,
    • miRNA,
    • p27