Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7.
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.
Dangi-Garimella
Surabhi
S
Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, IL 60637, USA.
Yun
Jieun
J
Eves
Eva M
EM
Newman
Martin
M
Erkeland
Stefan J
SJ
Hammond
Scott M
SM
Minn
Andy J
AJ
Rosner
Marsha Rich
MR
D000818:Animals; D045744:Cell Line, Tumor; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction
C488352:Lin-28 protein, mouse; C000715187:Lin28A protein, human; D035683:MicroRNAs; D016328:NF-kappa B; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D016601:RNA-Binding Proteins; C539308:Raf kinase inhibitory protein, mouse; C487931:mirnlet7 microRNA, human; D054769:G-Protein-Coupled Receptor Kinase 2