UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors

Authors

  • Peter E. Zage MD, PhD,

    Corresponding author
    1. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas
    2. Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas
    3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas
    • Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, 1102 Bates, Suite 1220, Houston, TX 77030

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    • The first 2 authors contributed equally to this article.

  • Natalie Sirisaengtaksin MS,

    1. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, Texas
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    • The first 2 authors contributed equally to this article.

  • Yin Liu PhD,

    1. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, Texas
    2. Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas
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  • Monica Gireud MS,

    1. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, Texas
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  • Brandon S. Brown BS,

    1. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, Texas
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  • Shana Palla MS,

    1. Division of Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Kristen N. Richards MD,

    1. Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Dennis P. M. Hughes MD, PhD,

    1. Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Andrew J. Bean PhD

    1. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, Texas
    2. Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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Abstract

BACKGROUND:

The UBE4B gene, which is located on chromosome 1p36, encodes a ubiquitin ligase that interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a protein involved in epidermal growth factor receptor (EGFR) trafficking, suggesting a link between EGFR trafficking and neuroblastoma pathogenesis. The authors analyzed the roles of UBE4B in the outcomes of patients with neuroblastoma and in neuroblastoma tumor cell proliferation, EGFR trafficking, and response to EGFR inhibition.

METHODS:

The association between UBE4B expression and the survival of patients with neuroblastoma was examined using available microarray data sets. UBE4B and EGFR protein levels were measured in patient tumor samples, EGFR degradation rates were measured in neuroblastoma cell lines, and the effects of UBE4B on neuroblastoma tumor cell growth were analyzed. The effects of the EGFR inhibitor cetuximab were examined in neuroblastoma cells that expressed wild-type and mutant UBE4B.

RESULTS:

Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma. UBE4B overexpression reduced neuroblastoma tumor cell proliferation, and UBE4B expression was inversely related to EGFR expression in tumor samples. EGFR degradation rates correlated with cellular UBE4B levels. Enhanced expression of catalytically active UBE4B resulted in reduced sensitivity to EGFR inhibition.

CONCLUSIONS:

The current study demonstrates associations between UBE4B expression and the outcomes of patients with neuroblastoma and between UBE4B and EGFR expression in neuroblastoma tumor samples. Moreover, levels of UBE4B influence neuroblastoma tumor cell proliferation, EGFR degradation, and response to EGFR inhibition. These results suggest UBE4B-mediated growth factor receptor trafficking may contribute to the poor prognosis of patients who have neuroblastoma tumors with 1p36 deletions and that UBE4B expression may be a marker that can predict responses of neuroblastoma tumors to treatment. Cancer 2013. © 2012 American Cancer Society.

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