Neuroblastoma patient outcomes, tumor differentiation, and ERK activation are correlated with expression levels of the ubiquitin ligase UBE4B
Sarah E. Woodfield1, Rong Jun Guo2,7, Yin Liu3,4, Angela M. Major2, Emporia Faith Hollingsworth2, Sandra Indiviglio1, Sarah B. Whittle1, Qianxing Mo5, Andrew J. Bean3, Michael Ittmann2,6, Dolores Lopez-Terrada1,2 and Peter E. Zage1
1 Department of Pediatrics, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
2 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
3 Department of Neurobiology and Anatomy, The University of Texas Medical School & Graduate School of Biomedical Sciences, Houston, TX, USA
4 Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
5 Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
6 The Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX, USA
7 Department of Pathology, University of Alabama Birmingham, Birmingham, AL, USA
Correspondence:
Peter E. Zage, email:
Keywords: neuroblastoma, UBE4B, differentiation, ERK, retinoic acid
Received: October 08, 2015 Accepted: February 14, 2016 Published: February 16, 2016
Abstract
Background
UBE4B is an E3/E4 ubiquitin ligase whose gene is located in chromosome 1p36.22. We analyzed the associations of UBE4B gene and protein expression with neuroblastoma patient outcomes and with tumor prognostic features and histology.
Methods
We evaluated the association of UBE4B gene expression with neuroblastoma patient outcomes using the R2 Platform. We screened neuroblastoma tumor samples for UBE4B protein expression using immunohistochemistry. FISH for UBE4B and 1p36 deletion was performed on tumor samples. We then evaluated UBE4B expression for associations with prognostic factors and with levels of phosphorylated ERK in neuroblastoma tumors and cell lines.
Results
Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma and with worse outcomes in all patient subgroups. UBE4B protein expression was associated with neuroblastoma tumor differentiation, and decreased UBE4B protein levels were associated with high-risk features. UBE4B protein levels were also associated with levels of phosphorylated ERK.
Conclusions
We have demonstrated associations between UBE4B gene expression and neuroblastoma patient outcomes and prognostic features. Reduced UBE4B protein expression in neuroblastoma tumors was associated with high-risk features, a lack of differentiation, and with ERK activation. These results suggest UBE4B may contribute to the poor prognosis of neuroblastoma tumors with 1p36 deletions and that UBE4B expression may mediate neuroblastoma differentiation.
