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Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7.
- Source :
-
The EMBO journal [EMBO J] 2009 Feb 18; Vol. 28 (4), pp. 347-58. Date of Electronic Publication: 2009 Jan 15. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Animals
Cell Line, Tumor
G-Protein-Coupled Receptor Kinase 2 metabolism
Humans
MAP Kinase Signaling System
Male
Mice
NF-kappa B metabolism
Neoplasm Metastasis
Neoplasm Transplantation
Prostatic Neoplasms metabolism
Signal Transduction
MicroRNAs metabolism
Phosphatidylethanolamine Binding Protein metabolism
RNA-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2075
- Volume :
- 28
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 19153603
- Full Text :
- https://doi.org/10.1038/emboj.2008.294