Raf kinase inhibitory protein (RKIP) negatively regulates the MAP kinase (MAPK), G protein-coupled receptor kinase-2, and NF-κB 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.

Additional Metadata
Keywords Bagg albino mouse, LIN28, Let-7, MAP kinase, Metastasis, Myc protein, Raf kinase inhibitory protein, animal experiment, animal model, article, bone metastasis, breast cancer, cancer cell, cancer inhibition, cancer invasion, controlled study, enzyme inhibition, female, gene, gene expression, genetic transcription, high mobility group A2 protein, human, human cell, let 7 gene, metastasis, metastasis inhibition, mitogen activated protein kinase, molecular biology, mouse, nonhuman, nude mouse, phosphatidylethanolamine binding protein, priority journal, protein LIN28, protein depletion, regulatory mechanism, signal transduction, transcription factor Snail, unclassified drug
Persistent URL dx.doi.org/10.1038/emboj.2008.294, hdl.handle.net/1765/18464
Citation
Dangi-Garimella, S, Yun, J, Eves, E.M, Newman, M, Erkeland, S.J, Hammond, S.M, … Rosner, M.R. (2009). Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO Journal, 28(4), 347–358. doi:10.1038/emboj.2008.294