Jinlong Yin1,2,†, Gunwoo Park1,2,†, Tae Hoon Kim2, Jun Hee Hong2, Youn-Jae Kim2, Xiong Jin3, Sangjo Kang2, Ji-Eun Jung2,3, Jeong-Yub Kim4,5, Hyeongsun Yun1,2, Jeong Eun Lee1,11, Minkyung Kim1, Junho Chung6,7, Hyunggee Kim3, Ichiro Nakano8,9, Ho-Shin Gwak2, Heon Yoo1,2, Byong Chul Yoo10, Jong Heon Kim1,11, Eun-Mi Hur12,13, Jeongwu Lee14‡, Seung-Hoon Lee1,2*, Myung-Jin Park4*, Jong Bae Park1,2*
1 Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea, 2 Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea, 3 Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea, 4 Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea, 5 Department of Pathology, College of Medicine, Korea University, Seoul, Korea, 6 Department of Biochemistry and Molecular Biology, Seoul National University, College of Medicine, Seoul, Korea, 7 Department of Cancer Biology, Seoul National University College of Medicine, Seoul, Korea, 8 Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, United States of America, 9 James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America, 10 Colorectal Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyangi, Korea, 11 Cancer Cell and Molecular Biology Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea, 12 Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea, 13 Department of Neuroscience, Korea University of Science and Technology, Daejeon, Korea, 14 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
†These authors contributed equally to this work.
‡ JL is joint senior author on this work.
* Correspondence to : 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.
Author Summary
Malignant gliomas are among the most lethal types of cancer, due in part to the stem-celllike characteristics and invasive properties of the brain tumor cells. However, little is known about the underlying molecular mechanisms that govern such processes. Here, we identify pigment epithelium-derived factor (PEDF) as a critical factor controlling stemness and tumor progression in glioma stem cells. We found that PEDF is secreted from glioblastoma expressing EGFRvIII, a frequently occurring mutation in primary glioblastoma that yields a permanently activated epidermal growth factor receptor. We delineate an EGFRvIII-STAT3-PEDF signaling axis as a signature profile of highly malignant gliomas, which promotes self-renewal of glioma stem cells. Our results demonstrate a previously unprecedented function of PEDF and implicate potential therapeutic approaches against malignant gliomas.