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

PLoS biology (2015-05-21)
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 Hur, Jeongwu Lee, Seung-Hoon Lee, Myung-Jin Park, Jong Bae Park
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.

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