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.
Bibliographical noteFunding Information:
Acknowledgements. We thank Drs Jeremy Rich at Cleveland Clinic, Hideyuki Saya at Keio University, Harley I. Kornblum at UCLA, and Antonio E. Chiocca at Brigham and Women’s Hospital for constructive discussion and suggestions for this study. We also thank the members in the Kim and Nakano labs for constructive criticism for this paper. This work was supported in part by The American Cancer Society MRSG-08-108-01, NIH/NCI P01 CA163205, R21 CA175875, NIH/NINDS R01 NS083767, and R01 NS087913 (to IN); the National Research Foundation (NRF) of Korea grant funded by the Korean government (MEST; 2011-0017544, to HK); the Basic Science Research Program through the NRF of Korea (2011-0024089, to SHK); and the Institute of Life Science and Natural Resources grant of Korea University (to SO).
© 2015 Macmillan Publishers Limited.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology