Deregulation of FoxM1b leads to tumour metastasis

Hyun Jung Park, Galina Gusarova, Zebin Wang, Janai R. Carr, Jing Li, Ki Hyun Kim, Jin Qiu, Yoon Dong Park, Peter R. Williamson, Nissim Hay, Angela L. Tyner, Lester F. Lau, Robert H. Costa, Pradip Raychaudhuri

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)21-34
Number of pages14
JournalEMBO Molecular Medicine
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Keywords

  • Arf
  • FoxM1
  • Metastasis

ASJC Scopus subject areas

  • Molecular Medicine

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  • Cite this

    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., & Raychaudhuri, P. (2011). Deregulation of FoxM1b leads to tumour metastasis. EMBO Molecular Medicine, 3(1), 21-34. https://doi.org/10.1002/emmm.201000107