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Tumor Biology

, Volume 36, Issue 4, pp 2921–2928 | Cite as

Epidermal growth factor receptor variant III renders glioma cancer cells less differentiated by JAGGED1

  • Eun-Jung Kim
  • Sung-Ok Kim
  • Xiong Jin
  • Seok Won Ham
  • Jaebong Kim
  • Jae-Bong Park
  • Jae-Yong Lee
  • Sung-Chan Kim
  • Hyunggee Kim
Research Article

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.

Keywords

EGFRvIII Glioblastoma Glioma stem cells JAGGED1 MAPK signaling Radioresistance 

Notes

Acknowledgments

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

None

References

  1. 1.
    Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.CrossRefPubMedGoogle Scholar
  2. 2.
    Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313:144–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Hatanpaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. 2010;12:675–84.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci. 2009;16:748–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Vescovi AL, Galli R, Reynolds BA. Brain tumor stem cells. Nat Rev Cancer. 2006;6:425–36.CrossRefPubMedGoogle Scholar
  6. 6.
    Stopschinski BE, Beier CP, Beier D. Glioblastoma cancer stem cells—from concept to clinical application. Cancer Lett. 2013;338:32–40.CrossRefPubMedGoogle Scholar
  7. 7.
    Oh SY, Kim H. Molecular culprits generating brain tumor stem cells. Brain Tumor Res Treat. 2013;1:9–15.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Stockhausen MT, Kristoffersen K, Poulsen HS. The functional role of Notch signaling in human gliomas. Neuro Oncol. 2010;12:199–211.CrossRefPubMedGoogle Scholar
  9. 9.
    Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005;65:2353–63.CrossRefPubMedGoogle Scholar
  10. 10.
    Jeon HM, Kim SH, Jin X, Park JB, Kim SH, Joshi K, et al. Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression. Cancer Res. 2014;74:4482–92.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Emlet DR, Gupta P, Holgado-Madruga M, Del Vecchio CA, Mitra SS, Han SY, et al. Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III. Cancer Res. 2014;74:1238–49.CrossRefPubMedGoogle Scholar
  12. 12.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.CrossRefGoogle Scholar
  13. 13.
    Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1:269–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Ayuso-Sacido A, Moliterno JA, Kratovac S, Kapoor GS, O'Rourke DM, Holland EC, et al. Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells. J Neuro Oncol. 2010;97:323–37.CrossRefGoogle Scholar
  15. 15.
    Jeon HM, Jin X, Lee JS, Oh SY, Sohn YW, Park HJ, et al. Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling. Genes Dev. 2008;22:2028–33.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jin X, Yin J, Kim SH, Sohn YW, Beck S, Lim YC, et al. EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res. 2011;71:7125–34.CrossRefPubMedGoogle Scholar
  17. 17.
    Jin X, Kim SH, Jeon HM, Beck S, Sohn YW, Yin J, et al. Interferon regulatory factor 7 regulates glioma stem cells via interleukin-6 and Notch signalling. Brain. 2012;135:1055–69.CrossRefPubMedGoogle Scholar
  18. 18.
    Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117:3988–4002.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117:3846–56.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005;8:13–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Nyati MK, Morgan MA, Feng FY, Lawrence TS. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer. 2006;6:876–85.CrossRefPubMedGoogle Scholar
  22. 22.
    Toulany M, Lee KJ, Fattah KR, Lin YF, Fehrenbacher B, Schaller M, et al. Akt promotes post-irradiation survival of human tumor cells through initiation, progression, and termination of DNA-PKcs-dependent DNA double-strand break repair. Mol Cancer Res. 2012;10:945–57.CrossRefPubMedGoogle Scholar
  23. 23.
    Latha K, Li M, Chumbalkar V, Gururaj A, Hwang Y, Dakeng S, et al. Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. Int J Cancer. 2013;132:509–20.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010;28:17–28.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Eun-Jung Kim
    • 1
    • 2
  • Sung-Ok Kim
    • 3
  • Xiong Jin
    • 1
    • 2
  • Seok Won Ham
    • 1
  • Jaebong Kim
    • 3
    • 4
  • Jae-Bong Park
    • 3
    • 4
  • Jae-Yong Lee
    • 3
    • 4
  • Sung-Chan Kim
    • 3
    • 4
  • Hyunggee Kim
    • 1
    • 2
  1. 1.Department of Biotechnology, School of Life Sciences and BiotechnologyKorea UniversitySeoulSouth Korea
  2. 2.Institute of Life Science and Natural ResourcesKorea UniversitySeoulSouth Korea
  3. 3.Department of Biochemistry, College of MedicineHallym UniversityChuncheonSouth Korea
  4. 4.Institute of Cell Differentiation and Aging, College of MedicineHallym UniversityChuncheonSouth Korea

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