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EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma

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Abstract

Eph receptors and ephrin ligands are master regulators of oncogenic signaling required for proliferation, migration, and metastasis. Yet, Eph/ephrin expression and activity in medulloblastoma (MB), the most common malignant brain tumor of childhood, remains poorly defined. We hypothesized that Eph/ephrins are differentially expressed by sonic hedgehog (SHH) and non-SHH MB and that specific members contribute to the aggressive phenotype. Affymetrix gene expression profiling of 29 childhood MB, separated into SHH (N = 11) and non-SHH (N = 18), was performed followed by protein validation of selected Eph/ephrins in another 60 MB and two MB cell lines (DAOY, D556). Functional assays were performed using MB cells overexpressing or deleted for selected ephrins. We found EPHB4 and EFNA4 almost exclusively expressed by SHH MB, whereas EPHA2, EPHA8, EFNA1 and EFNA3 are predominantly expressed by non-SHH MB. The remaining family members, except EFNB1, are ubiquitously expressed by over 70–90 % MB, irrespective of subgroup. EFNB1 is the only member differentially expressed by 28 % of SHH and non-SHH MB. Corresponding protein expression for EphB/ephrinB1 and B2 was validated in MB. Only ephrinB2 was also detected in fetal cerebellum, indicating that EphB/ephrinB1 expression is MB-specific. EphrinB1 immunopositivity localizes to tumor cells within MB with the highest proliferative index. EphrinB1 overexpression promotes EphB activation, alters F-actin distribution and morphology, decreases adhesion, and significantly promotes proliferation. Either silencing or overexpression of ephrinB1 impairs migration. These results indicate that EphrinB1 is uniquely dysregulated in MB and promotes oncogenic responses in MB cells, implicating ephrinB1 as a potential target.

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Acknowledgments

Video microscopy results were obtained using the Integrated Cellular Imaging (ICI) Core Facility, Emory University Winship Cancer Institute. Funding support provided in part by National Institute Health R01CA111835 (TJM), CURE Childhood Cancer (NM), and the Georgia Research Alliance (TJM).

Ethical standards

The experiments comply with the current laws of the country in which they were performed.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Emory Children’s Center, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, 2015 Uppergate Drive NE, 4th Floor, Atlanta, GA, 30322, USA

    Nicole McKinney, Liangping Yuan, Hongying Zhang, Jingbo Liu & Tobey J. MacDonald

  2. Department of Neurology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Yoon-Jae Cho

  3. Department of Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Yoon-Jae Cho

  4. Institute of Neuropathology, University Hospital of Zurich, Schmelzbergstr 12, 8091, Zurich, Switzerland

    Elisabeth Rushing

  5. Department of Pathology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Matthew Schniederjan

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  1. Nicole McKinney
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  3. Hongying Zhang
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Correspondence to Tobey J. MacDonald.

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McKinney, N., Yuan, L., Zhang, H. et al. EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma. J Neurooncol 121, 109–118 (2015). https://doi.org/10.1007/s11060-014-1618-8

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  • DOI: https://doi.org/10.1007/s11060-014-1618-8

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