title: Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells.
abstract: Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the pro-survival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitin-dependent lysosomal degradation to facilitate the STAT3 activation in GSCs. CD9 is preferentially expressed in GSCs of human GBM tumors. Mass spectrometry analysis identified gp130 as an interacting protein of CD9 in GSCs, which was confirmed by immunoprecipitation and immunofluorescent analyses. Disrupting CD9 or gp130 by shRNA significantly inhibited the self-renewal and promoted the differentiation of GSCs. Moreover, CD9 disruption markedly reduced gp130 protein levels and STAT3 activating phosphorylation in GSCs. CD9 stabilized gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote the BMX-STAT3 signaling in GSCs. Importantly, targeting CD9 potently inhibited GSC tumor growth in vivo, while ectopic expression of the constitutively activated STAT3 (STAT3-C) restored the tumor growth impaired by CD9 disruption. Collectively, we uncovered a critical regulatory mechanism mediated by tetraspanin CD9 to maintain the stem cell-like property and tumorigenic potential of GSCs.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.|The Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.|The Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.|The Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: He
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.|The Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Senlin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.|The Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Ping
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.|The Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D008247:Lysosomes / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000032:analysis / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D060245:Tetraspanin 29 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C554869:CD9 protein, human; D010455:Peptides; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D060245:Tetraspanin 29; D025801:Ubiquitin; D050822:Cytokine Receptor gp130