Stable interference of EWS–FLI1 in an Ewing sarcoma cell line impairs IGF-1/IGF-1R signalling and reveals TOPK as a new target
| Autor: | Christopher Poremba, G. Caballero, José Luis Ordóñez, D. Herrero-Martin, Carlos Mackintosh, V. Sevillano, J. Madoz-Gurpide, Karl-Ludwig Schaefer, Martin Eisenacher, Ana Pastora Otero-Motta, Daniel H. Wai, E. de Álava, Yvonne Braun, D. Osuna, A. S. Martins, Ana Teresa Amaral, M J Campos |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Oncogene Proteins Fusion TOPK Cell Down-Regulation Apoptosis Mice SCID Sarcoma Ewing Protein Serine-Threonine Kinases Biology Receptor IGF Type 1 IGF-1/IGF-1R Mice Cell Movement Mice Inbred NOD stable shRNAi model RNA interference Cell Line Tumor Gene expression medicine Animals Humans Insulin-Like Growth Factor I Protein kinase A Molecular Diagnostics Transcription factor Mitogen-Activated Protein Kinase Kinases Proto-Oncogene Protein c-fli-1 ETS transcription factor family fungi medicine.anatomical_structure Oncology FLI1 EWS–FLI1 Cancer research Female RNA Interference RNA-Binding Protein EWS Signal transduction Ewing sarcoma Signal Transduction Transcription Factors |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.-- et al. [BACKGROUND]: Ewing sarcoma is a paradigm of solid tumour -bearing chromosomal translocations resulting in fusion proteins that act as deregulated transcription factors. Ewing sarcoma translocations fuse the EWS gene with an ETS transcription factor, mainly FLI1. Most of the EWS-FLI1 target genes still remain unknown and many have been identified in heterologous model systems. [METHODS]: We have developed a stable RNA interference model knocking down EWS-FLI1 in the Ewing sarcoma cell line TC71. Gene expression analyses were performed to study the effect of RNA interference on the genetic signature of EWS-FLI1 and to identify genes that could contribute to tumourigenesis. [RESULTS]: EWS-FLI1 inhibition induced apoptosis, reduced cell migratory and tumourigenic capacities, and caused reduction in tumour growth. IGF-1 was downregulated and the IGF-1/IGF-1R signalling pathway was impaired. PBK/TOPK (T-LAK cell-originated protein kinase) expression was decreased because of EWS-FLI1 inhibition. We showed that TOPK is a new target gene of EWS-FLI1. TOPK inhibition prompted a decrease in the proliferation rate and a dramatic change in the cell's ability to grow in coalescence. [CONCLUSION]: This is the first report of TOPK activity in Ewing sarcoma and suggests a significant role of this MAPKK-like protein kinase in the Ewing sarcoma biology. © 2009 Cancer Research. CIC-IBMCC and HHU belong to NoE Eurobonet, FP6-2004-Lifescihealth-5, proposal number 018814, European Commission. Work at CIC is also funded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation-FEDER (PI052524; RD06/0020/0059, CD6/ 00001). Herrero-Martín was a recipient of a pre-doctoral fellowship from the Departamento de Educación, Junta de Castilla y León, Spain. This work has been done within the Acción Transversal en Cáncer program and the cooperative agreement between ISCIII and FICUS. |
| Databáze: | OpenAIRE |
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