Acquisition of an oncogenic fusion protein is sufficient to globally alter the landscape of miRNA expression to inhibit myogenic differentiation
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Jacob M. Loupe3,*, Patrick J. Miller4,*, Judy S. Crabtree1, Jovanny Zabaleta2 and Andrew D. Hollenbach1
1Louisiana State University Health Sciences Center, Department of Genetics, New Orleans, LA 70112, USA
2Louisiana State University Health Sciences Center, Department of Pediatrics and Stanley S. Scott Cancer Center, New Orleans, LA 70112, USA
3Current/Present address: Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, MA 02114, USA
4Current/Present address: Tulane University, New Orleans, LA 70112, USA
*These authors have contributed equally to this work
Andrew D. Hollenbach, email: [email protected]
Keywords: Alveolar Rhabdomyosarcoma, myogenesis, PAX3-FOXO1
Received: April 28, 2017 Accepted: July 03, 2017 Published: July 29, 2017
The differentiation status of tumors is used as a prognostic indicator, with tumors comprised of less differentiated cells exhibiting higher levels of aggressiveness that correlate with a poor prognosis. Although oncogenes contribute to blocking differentiation, it is not clear how they globally alter miRNA expression during differentiation to achieve this result. The pediatric sarcoma Alveolar Rhabdomyosarcoma, which is primarily characterized by the expression of the PAX3-FOXO1 oncogenic fusion protein, consists of undifferentiated muscle cells. However, it is unclear what role PAX3-FOXO1 plays in promoting the undifferentiated state. We demonstrate that expression of PAX3-FOXO1 globally alters the expression of over 80 individual miRNA during early myogenic differentiation, resulting in three primary effects: 1) inhibition of the expression of 51 miRNA essential for promoting myogenesis, 2) promoting the aberrant expression of 43 miRNA not normally expressed during myogenesis, and 3) altering the expression pattern of 39 additional miRNA. Combined, these changes are predicted to have an overall negative effect on myogenic differentiation. This is one of the first studies describing how an oncogene globally alters miRNA expression to block differentiation and has clinical implications for the development of much needed multi-faceted tumor-specific therapeutic regimens.
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