Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer

Karoliina Vuoriluoto, H. Haugen, S. Kiviluoto, John Mpindi, Jonna Nevo, C. Gjerdrum, C. Tiron, J.B. Lorens, Johanna Ivaska (Corresponding Author)

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369 Citations (Scopus)

Abstract

Epithelial-to-mesenchymal transition (EMT) is a critical event in the progression toward cancer metastasis. The intermediate filament protein vimentin is an important marker of EMT and a requisite regulator of mesenchymal cell migration. However, it is not known how vimentin functionally contributes to cancer cell invasion. Here, we report that ectopic expression of oncogenic H-Ras-V12G and Slug induces vimentin expression and migration in pre-malignant breast epithelial cells. Conversely, vimentin expression is necessary for Slug- or H-Ras-V12G-induced EMT-associated migration. Furthermore, silencing of vimentin in breast epithelial cells results in specific changes in invasiveness-related gene expression including upregulation of RAB25 (small GTPase Rab25) and downregulation of AXL (receptor tyrosine kinase Axl), PLAU (plasminogen activator, urokinase) and ITGB4 (integrin ?4-subunit). Importantly, gene expression profiling analyses reveal that vimentin expression correlates positively/negatively with these genes also in multiple breast cancer cell lines and breast cancer patient samples. Focusing on the tyrosine kinase Axl, we show that induction of vimentin by EMT is associated with upregulation of Axl expression and that Axl enhances the migratory activity of pre-malignant breast epithelial cells. Using null and knock-down cells and overexpression models, we also show that regulation of breast cancer cell migration in two- and three-dimensional matrices by vimentin is Axl- dependent and that Axl functionally contributes to lung extravasation of breast cancer cells in mice. In conclusion, our data show that vimentin functionally contributes to EMT and is required for induction of Axl expression. Moreover, these results provide a molecular explanation for vimentin-dependent cancer cell migration during EMT by identifying Axl as a key proximal component in this process
Original languageEnglish
Pages (from-to)1436-1448
JournalOncogene
Volume30
Issue number12
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Keywords

  • vimentin
  • EMT
  • Axl

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    Vuoriluoto, K., Haugen, H., Kiviluoto, S., Mpindi, J., Nevo, J., Gjerdrum, C., Tiron, C., Lorens, J. B., & Ivaska, J. (2011). Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene, 30(12), 1436-1448. https://doi.org/10.1038/onc.2010.509