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Author Notes:

Sana D. Karam, e-mail: sana.karam@ucdenver.edu

We thank James Olson's laboratory at the Fred Hutchinson Cancer Research Center (Seattle, WA, USA) for providing us with the ND2-SmoA1 medulloblastoma mouse model.

We also thank Lisa Hull, Xiumei Zhao, (Department of Biology, Georgetown University, Washington, DC, USA) Xueping Zhang and Alfredo Velena (Department of Radiation Medicine, Georgetown University Medical Center, Washington, DC, USA) for their technical assistance.

We thank Sujatha Venkataraman and Dr. Rajeev Vibhakar for helpful discussions and for sharing some of their resources and protocols with us.

The MRI imaging was performed in the Lombardi Preclinical Imaging Research laboratory (PIRL), flow cytometry was performed in the Lombardi Flow Cytometry Shared Resource (FCSR) and University of Colorado Cancer Center Flow Cytometry Shared Resource (FCSR).

The authors declare they have no conflict of interest.

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Research Funding:

This work was supported by the Paul Calabresi Career Development Award for Clinical Oncology (K12) and American Cancer Society Institutional Grant (SDK), NIH grant P01CA138390 (EBP), NIH P30 CA51008 (LW) and ABCC (CA and TM).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • Eph
  • medulloblastoma
  • ATM
  • cell cycle
  • radiosensitization
  • TYROSINE KINASE
  • ATAXIA-TELANGIECTASIA
  • SIGNALING PATHWAY
  • GENETIC PROFILES
  • CDK INHIBITOR
  • CANCER
  • PROLIFERATION
  • ACTIVATION
  • EXPRESSION
  • INVASION

Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization

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Journal Title:

Oncotarget

Volume:

Volume 6, Number 11

Publisher:

, Pages 8929-8946

Type of Work:

Article | Final Publisher PDF

Abstract:

The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.

Copyright information:

© 2015 Bhatia et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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