Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer
| Autor: | Johanna Ivaska, James B. Lorens, Christine Gjerdrum, John Mpindi, Hallvard Haugen, Jonna Nevo, Kiviluoto S, Karoliina Vuoriluoto, Crina Tiron |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Epithelial-Mesenchymal Transition Mice Nude Breast Neoplasms Vimentin Oncogene Protein p21(ras) Biology Mice 03 medical and health sciences 0302 clinical medicine vimentin SDG 3 - Good Health and Well-being Cell Movement Cell Line Tumor Proto-Oncogene Proteins Genetics medicine Animals Humans Epithelial–mesenchymal transition Molecular Biology 030304 developmental biology 0303 health sciences AXL receptor tyrosine kinase EMT Receptor Protein-Tyrosine Kinases Cancer Axl medicine.disease Xenograft Model Antitumor Assays Axl Receptor Tyrosine Kinase Cell biology 030220 oncology & carcinogenesis Cancer cell NIH 3T3 Cells Cancer research biology.protein Female Ectopic expression Snail Family Transcription Factors Tyrosine kinase Mesenchymal cell migration Transcription Factors |
| Zdroj: | 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, vol. 30, no. 12, pp. 1436-1448 . https://doi.org/10.1038/onc.2010.509 Oncogene |
| Popis: | 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 β4-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. |
| Databáze: | OpenAIRE |
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