Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells

Jinlong Yin, Gunwoo Park, Tae Hoon Kim, Jun Hee Hong, Youn Jae Kim, Xiong Jin, Sangjo Kang, Ji Eun Jung, Jeong Yub Kim, Hyeongsun Yun, Jeong Eun Lee, Minkyung Kim, Junho Chung, Hyunggee Kim, Ichiro Nakano, Ho Shin Gwak, Heon Yoo, Byong Chul Yoo, Jong Heon Kim, Eun Mi HurJeongwu Lee, Seung Hoon Lee, Myung Jin Park, Jong Bae Park

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35 Citations (Scopus)

Abstract

Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.

Original languageEnglish
Article numbere1002152
JournalPLoS biology
Volume13
Issue number5
DOIs
Publication statusPublished - 2015 May 20

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Yin, J., Park, G., Kim, T. H., Hong, J. H., Kim, Y. J., Jin, X., Kang, S., Jung, J. E., Kim, J. Y., Yun, H., Lee, J. E., Kim, M., Chung, J., Kim, H., Nakano, I., Gwak, H. S., Yoo, H., Yoo, B. C., Kim, J. H., ... Park, J. B. (2015). Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells. PLoS biology, 13(5), [e1002152]. https://doi.org/10.1371/journal.pbio.1002152