Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma. Neoplasia 2013 Sep;15(9):1049-63
Date
09/13/2013Pubmed ID
24027430Pubmed Central ID
PMC3769884DOI
10.1593/neo.13286Scopus ID
2-s2.0-84884378820 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
Pediatric rhabdomyosarcoma (RMS) is a morphologically and genetically heterogeneous malignancy commonly classified into three histologic subtypes, namely, alveolar, embryonal, and anaplastic. An issue that continues to challenge effective RMS patient prognosis is the dearth of molecular markers predictive of disease stage irrespective of tumor subtype. Our study involving a panel of 70 RMS tumors has identified specific alternative splice variants of the oncogenes Murine Double Minute 2 (MDM2) and MDM4 as potential biomarkers for RMS. Our results have demonstrated the strong association of genotoxic-stress inducible splice forms MDM2-ALT1 (91.6% Intergroup Rhabdomyosarcoma Study Group stage 4 tumors) and MDM4-ALT2 (90.9% MDM4-ALT2-positive T2 stage tumors) with high-risk metastatic RMS. Moreover, MDM2-ALT1-positive metastatic tumors belonged to both the alveolar (50%) and embryonal (41.6%) subtypes, making this the first known molecular marker for high-grade metastatic disease across the most common RMS subtypes. Furthermore, our results show that MDM2-ALT1 expression can function by directly contribute to metastatic behavior and promote the invasion of RMS cells through a matrigel-coated membrane. Additionally, expression of both MDM2-ALT1 and MDM4-ALT2 increased anchorage-independent cell-growth in soft agar assays. Intriguingly, we observed a unique coordination in the splicing of MDM2-ALT1 and MDM4-ALT2 in approximately 24% of tumor samples in a manner similar to genotoxic stress response in cell lines. To further explore splicing network alterations with possible relevance to RMS disease, we used an exon microarray approach to examine stress-inducible splicing in an RMS cell line (Rh30) and observed striking parallels between stress-responsive alternative splicing and constitutive splicing in RMS tumors.
Author List
Jacob AG, O'Brien D, Singh RK, Comiskey DF Jr, Littleton RM, Mohammad F, Gladman JT, Widmann MC, Jeyaraj SC, Bolinger C, Anderson JR, Barkauskas DA, Boris-Lawrie K, Chandler DSMESH terms used to index this publication - Major topics in bold
Alternative SplicingBiomarkers, Tumor
Cell Adhesion
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
DNA Damage
Humans
Nuclear Proteins
Protein Isoforms
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
Rhabdomyosarcoma
Stress, Physiological