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

PLoS Biol. 2015 May 20;13(5):e1002152. doi: 10.1371/journal.pbio.1002152. eCollection 2015 May.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication
  • Disease Progression
  • ErbB Receptors / metabolism*
  • Eye Proteins / metabolism*
  • Female
  • Glioma / etiology*
  • Glioma / metabolism
  • Glioma / mortality
  • HEK293 Cells
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms, Experimental / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Nerve Growth Factors / metabolism*
  • Receptors, Notch / metabolism
  • SOXB1 Transcription Factors / metabolism
  • STAT3 Transcription Factor / metabolism
  • Serpins / metabolism*

Substances

  • Eye Proteins
  • Nerve Growth Factors
  • Receptors, Notch
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Serpins
  • epidermal growth factor receptor VIII
  • pigment epithelium-derived factor
  • ErbB Receptors

Grants and funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2062555, JBP) and grant funded by the National Cancer Center, Republic of Korea (1210043, HYo; 1210042, SHL; 1210041, JBP, and 1510060-1, JBP) and grant funded by Nuclear Research & Development Program funded by the Korean Ministry of Science, ICT and Future Planning (MJP). NRF: http://www.nrf.re.kr. National Cancer Center: ncc.re.kr. Korean Ministry of Science, ICT and Future Planning: http://english.msip.go.kr/index.do. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.