Identification of PAX3‐FKHR‐regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: Focus on MYCN as a biologically relevant target
- 11 March 2008
- journal article
- research article
- Published by Wiley in Genes, Chromosomes and Cancer
- Vol. 47 (6), 510-520
- https://doi.org/10.1002/gcc.20554
Abstract
Rhabdomyosarcoma is a family of myogenic soft tissue tumors subdivided into two main subtypes: alveolar (ARMS) and embryonal (ERMS). ARMS is characterized by a frequent 2;13 chromosomal translocation that creates a PAX3‐FKHR fusion transcription factor. To identify downstream targets of PAX3‐FKHR, we introduced an inducible form of PAX3‐FKHR into human RD ERMS cells. Microarray analysis identified 39 genes (29 upregulated and 10 downregulated) that are modulated by PAX3‐FKHR in RD cells and differentially expressed between ERMS and PAX3‐FKHR‐positive ARMS tumors. Functional annotation demonstrated that genes involved in regulation of transcription and development, particularly neurogenesis, are represented in this group. MYCN was one notable neural‐related transcription factor‐encoding gene identified in this set, and its regulation by PAX3‐FKHR was further confirmed at the RNA and protein levels. The findings of cycloheximide inhibition and time‐course studies are consistent with the hypothesis that the PAX3‐FKHR protein acts directly on the MYCN gene at the transcriptional level. Functional studies established that MYCN cooperates with PAX3‐FKHR to enhance oncogenic activity. In conclusion, we identified a selected set of biologically relevant genes modulated by PAX3‐FKHR, and demonstrated that PAX3‐FKHR contributes to the expression of MYCN and in turn MYCN collaborates with PAX3‐FKHR in tumorigenesis.Keywords
This publication has 30 references indexed in Scilit:
- Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHROncogene, 2007
- Global gene expression profiling of PAX‐FKHR fusion‐positive alveolar and PAX‐FKHR fusion‐negative embryonal rhabdomyosarcomasThe Journal of Pathology, 2007
- Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar RhabdomyosarcomasCancer Research, 2006
- Examination of Gene Fusion Status in Archival Samples of Alveolar Rhabdomyosarcoma Entered on the Intergroup Rhabdomyosarcoma Study-III Trial: A Report from the Children's Oncology GroupThe Journal of Molecular Diagnostics, 2006
- Validation of Met as a Therapeutic Target in Alveolar and Embryonal RhabdomyosarcomaCancer Research, 2006
- Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoproteinOncogene, 2004
- Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophreniaMolecular Psychiatry, 2003
- Significance analysis of microarrays applied to the ionizing radiation responseProceedings of the National Academy of Sciences of the United States of America, 2001
- Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHROncogene, 2000
- Oncogene amplification in solid tumorsSeminars in Cancer Biology, 1999