Abstract 3983: The role of UBE4B in neuroblastoma pathogenesis
Authors: Indiviglio Sandra M. , Woodfield Sarah E. , Zhang Linna , Guo Rongjun , Lopez-Terrada Dolores , Bean Andrew J. , Zage Peter E. 
Published: May 2015

Abstract
Background: Neuroblastoma is the most common extracranial solid malignancy in children. Children with aggressive neuroblastoma have an overall survival rate of 30% using current treatment regimens. We recently identified an association between UBE4B gene expression and neuroblastoma patient outcomes. The UBE4B gene is found in the chromosome 1p36 region frequently deleted in neuroblastoma. UBE4B is an E3/E4 ubiquitin ligase involved in the degradation of membrane proteins, including growth factor receptors, and p53. Although the p53 pathway has been shown to be involved in neuroblastoma, the mechanisms underlying the role of UBE4B in neuroblastoma pathogenesis are not known. We previously identified an inverse correlation between EGFR and UBE4B protein expression in neuroblastoma patient tumor samples, suggesting that UBE4B-mediated protein degradation may be critical for neuroblastoma pathogenesis. Additionally, we identified an association between UBE4B gene expression and MYCN amplification, one of the strongest prognostic factors for high-risk neuroblastoma. Previous studies on UBE4B were based on mRNA and Western blotting analysis of frozen tissue specimens, and without addressing potential tumor heterogeneity, a striking feature of neuroblastoma. The purpose of this study was to further explore the role of UBE4B in pathogenesis and its association with other known prognostic factors in neuroblastoma tumors.
Experimental design and Results: Using immunohistochemistry, we evaluated UBE4B and EGFR protein expression in tissue specimens from neuroblastoma patient tumor samples. UBE4B expression was reduced in eighteen cases (51%). This reduction was only seen in poorly differentiated or undifferentiated tumors, or the poorly differentiated component of intermixed tumors. Additionally, tissue microarrays containing primary neuroblastoma tumors were analyzed for EGFR expression. Approximately 80% of the tumor samples contained high EGFR expression. Lastly, using coimmunoprecipitation analysis, we identified a potential interaction between UBE4B and p53.
Conclusions: We found reduced protein UBE4B expression to be a common event in neuroblastoma tumors. This reduced UBE4B expression was associated with a lack of differentiation in neuroblastoma tumors, a hallmark of aggressive malignancies. Furthermore, the potential interaction of UBE4B and p53 represents a novel mechanism to explain the association of UBE4B gene expression with neuroblastoma patient outcomes. Additional studies are underway to further explore these roles of UBE4B in neuroblastoma pathogenesis.
Citation Format: Sandra M. Indiviglio, Sarah E. Woodfield, Linna Zhang, Rongjun Guo, Dolores Lopez-Terrada, Andrew J. Bean, Peter E. Zage. The role of UBE4B in neuroblastoma pathogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3983. doi:10.1158/1538-7445.AM2014-3983