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  • The EMBO Journal (2009) 28, 347 - 358
  • doi:10.1038/emboj.2008.294

Published online: 15 January 2009

Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7

Surabhi Dangi-Garimella1,a, Jieun Yun1,a, Eva M Eves1, Martin Newman2, Stefan J Erkeland4, Scott M Hammond2, Andy J Minn3 and Marsha Rich Rosner1

  1. Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, IL, USA
  2. Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC, USA
  3. Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research, University of Chicago, IL, USA
  4. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

Correspondence to:

Marsha Rich Rosner, Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, W421C, 929 East 57th Street, Chicago, IL 60637, USA. Tel.: +1 773 702 0380; Fax: +1 773 702 4476; E-mail: m-rosner@uchicago.edu

aThese authors contributed equally to this work

Received 14 August 2008; Accepted 17 December 2008

Raf kinase inhibitory protein (RKIP) negatively regulates the MAP kinase (MAPK), G protein-coupled receptor kinase-2, and NF-kappaB signalling cascades. RKIP has been implicated as a metastasis suppressor for prostate cancer, but the mechanism is not known. Here, we show that RKIP inhibits invasion by metastatic breast cancer cells and represses breast tumour cell intravasation and bone metastasis in an orthotopic murine model. The mechanism involves inhibition of MAPK, leading to decreased transcription of LIN28 by Myc. Suppression of LIN28 enables enhanced let-7 processing in breast cancer cells. Elevated let-7 expression inhibits HMGA2, a chromatin remodelling protein that activates pro-invasive and pro-metastatic genes, including Snail. LIN28 depletion and let-7 expression suppress bone metastasis, and LIN28 restores bone metastasis in mice bearing RKIP-expressing breast tumour cells. These results indicate that RKIP suppresses invasion and metastasis in part through a signalling cascade involving MAPK, Myc, LIN28, let-7, and downstream let-7 targets. RKIP regulation of two pluripotent stem cell genes, Myc and LIN28, highlights the importance of RKIP as a key metastasis suppressor and potential therapeutic agent.

  • Keywords:

    • let-7,
    • LIN28,
    • metastasis,
    • MAP kinase,
    • raf kinase inhibitory protein