The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

S. H. Kim, E. J. Kim, M. Hitomi, S. Y. Oh, X. Jin, H. M. Jeon, S. Beck, X. Jin, J. K. Kim, C. G. Park, S. Y. Chang, J. Yin, T. Kim, Y. J. Jeon, J. Song, Y. C. Lim, J. D. Lathia, I. Nakano, H. Kim

    Research output: Contribution to journalArticlepeer-review

    39 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1517-1525
    Number of pages9
    JournalCell Death and Differentiation
    Volume22
    Issue number9
    DOIs
    Publication statusPublished - 2015 Sept 11

    Bibliographical note

    Publisher Copyright:
    © 2015 Macmillan Publishers Limited.

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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