title: Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.
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.
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Gunwoo
authors.initials: G
authors.lastname: Park
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Hong
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Youn-Jae
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Xiong
authors.initials: X
authors.lastname: Jin
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Sangjo
authors.initials: S
authors.lastname: Kang
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea; Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Jung
authors.affiliation: Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; Department of Pathology, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Jeong-Yub
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Hyeongsun
authors.initials: H
authors.lastname: Yun
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Cancer Cell and Molecular Biology Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University, College of Medicine, Seoul, Korea; Department of Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Chung
authors.affiliation: Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Hyunggee
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio, United States of America; James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Ho-Shin
authors.initials: HS
authors.lastname: Gwak
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Heon
authors.initials: H
authors.lastname: Yoo
authors.affiliation: Colorectal Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyangi, Korea.
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Cancer Cell and Molecular Biology Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Jong Heon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea; Department of Neuroscience, Korea University of Science and Technology, Daejeon, Korea.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Hur
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Divisions of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Jong Bae
authors.initials: JB
authors.lastname: Park
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D005910:Glioma / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D066246:ErbB Receptors; D005136:Eye Proteins; D009414:Nerve Growth Factors; D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors; D050796:STAT3 Transcription Factor; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C527782:SOX2 protein, human; C494086:STAT3 protein, human; C410723:epidermal growth factor receptor VIII