Oncotarget

Research Papers:

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

Shilpa Bhatia, Nimrah A. Baig, Olga Timofeeva, Elena B. Pasquale, Kellen Hirsch, Tobey J. MacDonald, Anatoly Dritschilo, Yi Chien Lee, Mark Henkemeyer, Brian Rood, Mira Jung, Xiao-Jing Wang, Marcel Kool, Olga Rodriguez, Chris Albanese and Sana D. Karam _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:8929-8946. https://doi.org/10.18632/oncotarget.3369

Metrics: PDF 1148 views  |   HTML 1171 views  |   ?  


Abstract

Shilpa Bhatia1,*, Nimrah A. Baig2,*, Olga Timofeeva2, Elena B. Pasquale3, Kellen Hirsch1, Tobey J. MacDonald4, Anatoly Dritschilo2,7, Yi Chien Lee2, Mark Henkemeyer5, Brian Rood6, Mira Jung2, Xiao-Jing Wang8, Marcel Kool9, Olga Rodriguez2,*, Chris Albanese2,10,*, Sana D. Karam1,2,*

1Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA

2Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

3Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA

4Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA

5Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

6Children’s National Medical Center, Washington DC 20010, USA

7Georgetown University Hospital, Washington, DC, 20007, USA

8Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA

9Division of Pediatric Neurooncology, German Cancer Research Center DKFZ, Heidelberg, Germany

10Department of Pathology, Georgetown University School of Medicine, Washington, DC 20057, USA

*These authors have contributed equally to this work

Correspondence to:

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

Keywords: Eph, medulloblastoma, ATM, cell cycle, radiosensitization

Received: December 05, 2014     Accepted: February 11, 2015     Published: March 30, 2015

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 3369