Stress-Induced Isoforms of MDM2 and MDM4 Correlate with High-Grade Disease and an Altered Splicing Network in Pediatric Rhabdomyosarcoma

• DOI: 10.1593/neo.13286
• Publication Date: 2015-04-23T13:11:10Z
• Authors: Aishwarya G. Jacob; Dennis O'Brien; Ravi K. Singh; Daniel F. Comiskey; Robert M. Littleton; Fuad Mohammad; Jordan T. Gladman; Maria C. Widmann; Selvi C. Jeyaraj; Cheryl Bolinger; James R. Anderson; Donald A. Barkauskas; Kathleen Boris-La...; Dawn S. Chandler
• Keywords: 0303 health sciences; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Nuclear Proteins; Cell Cycle Proteins; Proto-Oncogene Proteins c-mdm2; Alternative Splicing; 03 medical and health sciences; Stress, Physiological; Cell Line, Tumor; Proto-Oncogene Proteins; Rhabdomyosarcoma; Biomarkers, Tumor; Cell Adhesion; Humans; Protein Isoforms; RC254-282; Cell Proliferation; DNA Damage

Pediatric rhabdomyosarcoma (RMS) is a morphologically and genetically heterogeneous malignancy commonly classified into three histologic subtypes, namely, alveolar, embryonal, anaplastic. An issue that continues to challenge effective RMS patient prognosis the dearth of molecular markers predictive disease stage irrespective tumor subtype. Our study involving panel 70 tumors has identified specific alternative splice variants oncogenes Murine Double Minute 2 (MDM2) MDM4 as potential biomarkers for RMS. results have demonstrated strong association genotoxic-stress inducible forms MDM2-ALT1 (91.6% Intergroup Rhabdomyosarcoma Study Group 4 tumors) MDM4-ALT2 (90.9% MDM4-ALT2-positive T2 with high-risk metastatic Moreover, MDM2-ALT1-positive belonged both alveolar (50%) embryonal (41.6%) making this first known marker high-grade across most common subtypes. Furthermore, our show expression can function by directly contribute behavior promote invasion cells through matrigel-coated membrane. Additionally, increased anchorage-independent cell-growth in soft agar assays. Intriguingly, we observed unique coordination splicing approximately 24% samples manner similar genotoxic stress response cell lines. To further explore network alterations possible relevance disease, used an exon microarray approach examine stress-inducible line (Rh30) striking parallels between stress-responsive constitutive tumors.