Epidermal growth factor receptor variant III renders glioma cancer cells less differentiated by JAGGED1
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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.
KeywordsEGFRvIII Glioblastoma Glioma stem cells JAGGED1 MAPK signaling Radioresistance
We would like to thank all members of the Cell Growth Regulation Lab for the helpful discussion and technical assistance. This work was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (No. 2010-0025204 to S.C. Kim) and by the National Nuclear Technology Program through the NRF of Korea funded by the Ministry of Science, ICT, and Future Planning (No. 2013M2A2A7042530 to H. Kim). S.W. Ham was supported by Kwanjeong Educational Foundation Domestic Scholarship.
Conflicts of interest