RESUMO
The mechanism whereby the fusion of EWSR1 with the ETS transcription factor FLI1 contributes to malignant transformation in Ewing sarcoma remains unclear. We show that injection of human or zebrafish EWSR1/FLI1 mRNA into developing zebrafish embryos leads to mitotic defects with multipolar and disorganized mitotic spindles. Expression of human EWSR1/FLI1 in HeLa cells also results in mitotic defects, along with mislocalization of Aurora kinase B, a key regulator of mitotic progression. Because these mitotic abnormalities mimic those observed with the knockdown of EWSR1 in zebrafish embryos and HeLa cells, we investigated whether EWSR1/FLI1 interacts with EWSR1 and interferes with its function. EWSR1 coimmunoprecipitates with EWSR1/FLI1, and overexpression of EWSR1 rescues the mitotic defects in EWSR1/FLI1-transfected HeLa cells. This interaction between EWSR1/FLI1 and EWSR1 in Ewing sarcoma may induce mitotic defects leading to genomic instability and subsequent malignant transformation.
Assuntos
Proteínas de Ligação a Calmodulina/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteínas de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Proteínas de Peixe-Zebra/genética , Animais , Proteínas de Ligação a Calmodulina/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Embrião não Mamífero/patologia , Instabilidade Genômica , Células HeLa , Humanos , Mitose/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , RNA Mensageiro/genética , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/metabolismo , Sarcoma de Ewing/veterinária , Transfecção , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
A peripheral neuroblastoma was found in the abdominal cavity of a young male beagle dog. The large tumor mass involved the left kidney and both adrenal glands. Histologically, a major portion of the neoplasm consisted of lobulated sheets of small round cells with hyperchromatic nuclei mixed with polygonal cells and neuropil. Small clusters of polygonal cells with abundant eosinophilic cytoplasm and a trabecular growth pattern were observed adjacent to some of the tumor lobules. Small, round neoplastic cells metastasized to lumbar lymph nodes and also to the adrenal glands. The neoplastic cells were positive for neuron-specific enolase, synaptophysin, and neurofilament protein. Electron micrographs revealed intracytoplasmic dense core granules, microtubules, intermediate filaments, and desmosomes in the cytoplasm of the neoplastic cells.
