Caveolin-1 (Cav1) is a Target of Ews/Fli-1 and a Key Determinant of the Oncogenic Phenotype and Tumorigenicity of Ewing's Sarcoma Cells.
From: Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, Georgetown University Medical Center, Washington, DC 20057, USA.
Cancer research
- Publish Date: Oct 2006
- ISSN: 0008-5472
- Volume: 66
- Issue: 20
- Pages: 9937-47
- Medium: Print
- Language: English
- Citation (JAMA): Tirado Oscar M, Mateo-Lozano Silvia, Villar Joaquín, et al. Caveolin-1 (Cav1) is a Target of Ews/Fli-1 and a Key Determinant of the Oncogenic Phenotype and Tumorigenicity of Ewing's Sarcoma Cells.. Cancer Res. Oct 2006;66:9937-47
Abstract
Tumors of the Ewing’s sarcoma family (ESFT), such as Ewing’s sarcoma (EWS) and primitive neuroectodermal tumors (PNET), are highly aggressive malignancies predominantly affecting children and young adults. ESFT express chimeric transcription factors encoded by hybrid genes fusing the EWS gene with several ETS genes, most commonly FLI-1. EWS/FLI-1 proteins are responsible for the malignant phenotype of ESFT, but only few of their transcriptional targets are known. Using antisense and short hairpin RNA-mediated gene expression knockdown, array analyses, chromatin immunoprecipitation methods, and reexpression studies, we show that caveolin-1 (CAV1) is a new direct target of EWS/FLI-1 that is overexpressed in ESFT cell lines and tumor specimens and is necessary for ESFT tumorigenesis. CAV1 knockdown led to up-regulation of Snail and the concomitant loss of E-cadherin expression. Consistently, loss of CAV1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of EWS cell-derived tumors in nude mice xenografts, indicating that CAV1 promotes the malignant phenotype in EWS carcinogenesis. Reexpression of CAV1 or E-cadherin in CAV1 knockdown EWS cells rescued the oncogenic phenotype of the original EWS cells, showing that the CAV1/Snail/E-cadherin pathway plays a central role in the expression of the oncogenic transformation functions of EWS/FLI-1. Overall, these data identify CAV1 as a key determinant of the tumorigenicity of ESFT and imply that targeting CAV1 may allow the development of new molecular therapeutic strategies for ESFT patients.
Mesh Headings (Keywords): Animals, Cadherins, Caveolin 1, Cell Adhesion, Cell Growth Processes, Cell Line, Tumor, Chromatin Immunoprecipitation, Down-Regulation, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Oncogene Proteins, Fusion, Proto-Oncogene Protein c-fli-1, RNA, Antisense, Sarcoma, Ewing’s, Transcription Factors, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 17047056
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.