title: The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells.
abstract: Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.
authors.affiliation: 1] School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea [2] Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hitomi
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: H-M
authors.initials: HM
authors.lastname: Jeon
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: S
authors.initials: S
authors.lastname: Beck
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: J-K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: C G
authors.initials: CG
authors.lastname: Park
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: J
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul 143-752, Republic of Korea.
authors.forename: Y C
authors.initials: YC
authors.lastname: Lim
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA [3] Case Comprehensive Cancer Center, Cleveland, OH 44195, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: 1] Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA [2] James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: I
authors.initials: I
authors.lastname: Nakano
authors.affiliation: School of Life Sciences and Biotechnology and Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins