EWS-FLI1 Fusion Protein Up-regulates Critical Genes in Neural Crest Development and Is Responsible for the Observed Phenotype of Ewing's Family of Tumors Export

@article{citeulike:4501857, abstract = {Tumor-specific translocations are common in tumors of mesenchymal origin. Whether the translocation determines the phenotype, or vice versa, is debatable. Ewing's family tumors (EFT) are consistently associated with an EWS-FLI1 translocation and a primitive neural phenotype. Histogenesis and classification are therefore uncertain. To test whether EWS-FLI1 fusion gene expression is responsible for the primitive neuroectodermal phenotype of EFT, we established a tetracycline-inducible EWS-FLI1 expression system in a rhabdomyosarcoma cell line RD. Cell morphology changed after EWS-FLI1 expression, resembling cultured EFT cells. Xenografts showed typical EFT features, distinct from tumors formed by parental RD. Neuron-specific microtubule gene MAPT, parasympathetic marker cholecystokinin, and epithelial marker keratin 18 were up-regulated. Conversely, myogenesis was diminished. Comparison of the up-regulated genes in RD-EF with the Ewing's signature genes identified important EWS-FLI1 downstream genes, many involved in neural crest differentiation. These results were validated by real-time reverse transcription-PCR analysis and RNA interference technology using small interfering RNA against EWS-FLI1 breakpoint. The present study shows that the neural phenotype of Ewing's tumors is attributable to the EWS-FLI1 expression and the resultant phenotype resembles developing neural crest. Such tumors have a limited neural phenotype regardless of tissue of origin. These findings challenge traditional views of histogenesis and tumor origin. 10.1158/0008-5472.CAN-04-2857}, author = {Hu-Lieskovan, Siwen and Zhang, Jingsong and Wu, Lingtao and Shimada, Hiroyuki and Schofield, Deborah E. and Triche, Timothy J.}, citeulike-article-id = {4501857}, citeulike-linkout-0 = {http://dx.doi.org/10.1158/0008-5472.CAN-04-2857}, citeulike-linkout-1 = {http://cancerres.aacrjournals.org/cgi/content/abstract/65/11/4633}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/15930281}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=15930281}, doi = {10.1158/0008-5472.CAN-04-2857}, journal = {Cancer Res}, keywords = {ewings\_sarcoma, ews-fli1, malignant\_transformation, paper}, month = {June}, number = {11}, pages = {4633--4644}, posted-at = {2009-05-11 05:21:18}, priority = {3}, title = {EWS-FLI1 Fusion Protein Up-regulates Critical Genes in Neural Crest Development and Is Responsible for the Observed Phenotype of Ewing's Family of Tumors}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-04-2857}, volume = {65}, year = {2005} }

TY - JOUR ID - citeulike:4501857 L3 - citeulike-article-id:4501857 N2 - Tumor-specific translocations are common in tumors of mesenchymal origin. Whether the translocation determines the phenotype, or vice versa, is debatable. Ewing's family tumors (EFT) are consistently associated with an EWS-FLI1 translocation and a primitive neural phenotype. Histogenesis and classification are therefore uncertain. To test whether EWS-FLI1 fusion gene expression is responsible for the primitive neuroectodermal phenotype of EFT, we established a tetracycline-inducible EWS-FLI1 expression system in a rhabdomyosarcoma cell line RD. Cell morphology changed after EWS-FLI1 expression, resembling cultured EFT cells. Xenografts showed typical EFT features, distinct from tumors formed by parental RD. Neuron-specific microtubule gene MAPT, parasympathetic marker cholecystokinin, and epithelial marker keratin 18 were up-regulated. Conversely, myogenesis was diminished. Comparison of the up-regulated genes in RD-EF with the Ewing's signature genes identified important EWS-FLI1 downstream genes, many involved in neural crest differentiation. These results were validated by real-time reverse transcription-PCR analysis and RNA interference technology using small interfering RNA against EWS-FLI1 breakpoint. The present study shows that the neural phenotype of Ewing's tumors is attributable to the EWS-FLI1 expression and the resultant phenotype resembles developing neural crest. Such tumors have a limited neural phenotype regardless of tissue of origin. These findings challenge traditional views of histogenesis and tumor origin. 10.1158/0008-5472.CAN-04-2857 IS - 11 JF - Cancer Res EP - 4644 TI - EWS-FLI1 Fusion Protein Up-regulates Critical Genes in Neural Crest Development and Is Responsible for the Observed Phenotype of Ewing's Family of Tumors VL - 65 SP - 4633 KW - ewings_sarcoma KW - ews-fli1 KW - malignant_transformation KW - paper AU - Hu-Lieskovan, Siwen AU - Zhang, Jingsong AU - Wu, Lingtao AU - Shimada, Hiroyuki AU - Schofield, Deborah AU - Triche, Timothy PY - 2005/06/01/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-04-2857 ER -