RESUMEN
CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPß isoforms while re-expression of EWS-FLI1 rescued C/EBPß expression. Overexpression of C/EBPß-1, the largest of the three C/EBPß isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPß decreased colony formation, and re-expression of either C/EBPß-1 or C/EBPß-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPß in Ewing sarcoma. Furthermore, increased expression of C/EBPß led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPß-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance.
Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT/genética , Transformación Celular Neoplásica/genética , Resistencia a Antineoplásicos/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Familia de Aldehído Deshidrogenasa 1 , Antineoplásicos/farmacología , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Unión Proteica , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismo , Retinal-Deshidrogenasa , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/metabolismoRESUMEN
It is well known that children and young adults with neurofibromatosis type 1 (NF1) have a higher risk for non-neurogenic sarcomas than the general population, in addition to an increased risk for malignant peripheral nerve sheath tumor. When non-neurogenic sarcomas occur in early childhood, a subsequent malignant peripheral nerve sheath tumor can occur as a second malignant neoplasm, especially after alkylating agent chemotherapy and irradiation. This report includes the clinicopathologic features of non-neurogenic sarcomas and secondary malignant peripheral nerve sheath tumor in the context of four cases of NF1. The purpose is to emphasize that early diagnosis of NF1 and recognition of potential manifestations of non-neurogenic sarcomas are important for clinical care of these patients and their families.
