Both authors contributed equally to this work.
Deregulation of FoxM1b leads to tumour metastasis
Article first published online: 17 DEC 2010
Copyright © 2011 EMBO Molecular Medicine
EMBO Molecular Medicine
Volume 3, Issue 1, pages 21–34, January 2011
How to Cite
Park, H. J., Gusarova, G., Wang, Z., Carr, J. R., Li, J., Kim, K.-H., Qiu, J., Park, Y.-D., Williamson, P. R., Hay, N., Tyner, A. L., Lau, L. F., Costa, R. H. and Raychaudhuri, P. (2011), Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol Med, 3: 21–34. doi: 10.1002/emmm.201000107
- Issue published online: 4 JAN 2011
- Article first published online: 17 DEC 2010
- Accepted manuscript online: 22 NOV 2010 03:55AM EST
- Manuscript Accepted: 16 NOV 2010
- Manuscript Revised: 11 NOV 2010
- Manuscript Received: 15 MAY 2010
The forkhead box M1b (FoxM1b) transcription factor is over-expressed in human cancers, and its expression often correlates with poor prognosis. Previously, using conditional knockout strains, we showed that FoxM1b is essential for hepatocellular carcinoma (HCC) development. However, over-expression of FoxM1b had only marginal effects on HCC progression. Here we investigated the effect of FoxM1b expression in the absence of its inhibitor Arf. We show that transgenic expression of FoxM1b in an Arf-null background drives hepatic fibrosis and metastasis of HCC. We identify novel mechanisms of FoxM1b that are involved in epithelial–mesenchymal transition, cell motility, invasion and a pre-metastatic niche formation. FoxM1b activates the Akt-Snail1 pathway and stimulates expression of Stathmin, lysyl oxidase, lysyl oxidase like-2 and several other genes involved in metastasis. Furthermore, we show that an Arf-derived peptide, which inhibits FoxM1b, impedes metastasis of the FoxM1b-expressing HCC cells. The observations indicate that FoxM1b is a potent activator of tumour metastasis and that the Arf-mediated inhibition of FoxM1b is a critical mechanism for suppression of tumour metastasis.