title: Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization.
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.
authors: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors: Shilpa
authors: S
authors: Bhatia
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors: Nimrah A
authors: NA
authors: Baig
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors: Olga
authors: O
authors: Timofeeva
authors: Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors: Elena B
authors: EB
authors: Pasquale
authors: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors: Kellen
authors: K
authors: Hirsch
authors: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors: Tobey J
authors: TJ
authors: MacDonald
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.|Georgetown University Hospital, Washington, DC, USA.
authors: Anatoly
authors: A
authors: Dritschilo
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors: Yi Chien
authors: YC
authors: Lee
authors: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: Mark
authors: M
authors: Henkemeyer
authors: Children's National Medical Center, Washington DC, USA.
authors: Brian
authors: B
authors: Rood
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors: Mira
authors: M
authors: Jung
authors: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors: Xiao-Jing
authors: XJ
authors: Wang
authors: Division of Pediatric Neurooncology, German Cancer Research Center DKFZ, Heidelberg, Germany.
authors: Marcel
authors: M
authors: Kool
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors: Olga
authors: O
authors: Rodriguez
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.|Department of Pathology, Georgetown University School of Medicine, Washington, DC, USA.
authors: Chris
authors: C
authors: Albanese
authors: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.|Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors: Sana D
authors: SD
authors: Karam
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018572:Disease-Free Survival; D016193:G1 Phase; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D008527:Medulloblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D036225:Receptor, EphB1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D019012:Integrin beta1; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D036225:Receptor, EphB1; D016392:Proto-Oncogene Proteins pp60(c-src)
keywords: ATM; Eph; cell cycle; medulloblastoma; radiosensitization