title: Epidermal growth factor receptor variant III renders glioma cancer cells less differentiated by JAGGED1.
abstract: Glioblastoma is a highly aggressive primary brain tumor in which the majority of cancer cells are undifferentiated. One of the most common oncogenic drivers for this malignancy is the epidermal growth factor receptor variant III (EGFRvIII), which lacks a portion of the extracellular ligand-binding domain due to deletion of exons 2-7 of the EGFR gene. EGFRvIII plays a critical role in tumor progression, promoting acquisition of stem cell-like features including an undifferentiated state and therapy resistance. However, the molecular mechanisms by which EGFRvIII contributes to cancer cell aggressiveness remain poorly understood. Here, we show that EGFR expression correlates with JAGGED1 expression in glioblastoma patients. Overexpression of EGFRvIII in glioma cell lines augmented JAGGED1 expression at the transcriptional level through the mitogen-activated protein kinase signaling pathway. Consequently, EGFRvIII overexpression drove partial dedifferentiation of glioma cells, as determined by tumorsphere-forming ability and expression of stem cell markers, through JAGGED1 induction. EGFRvIII-mediated radioresistance, but not chemoresistance, was also modulated by JAGGED1. Taken together, our results provide new insight into the mechanism underlying EGFRvIII-driven glioblastoma aggressiveness.
authors.affiliation: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Sung-Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: Xiong
authors.initials: X
authors.lastname: Jin
authors.forename: Seok Won
authors.initials: SW
authors.lastname: Ham
authors.forename: Jaebong
authors.initials: J
authors.lastname: Kim
authors.forename: Jae-Bong
authors.initials: JB
authors.lastname: Park
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Sung-Chan
authors.initials: SC
authors.lastname: Kim
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases