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, Hyunggee Kim

Research output: Contribution to journalArticle

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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 Sep 11

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Glioma
Transcription Factors
Stem Cells
Glioblastoma
Phenotype
Astrocytes
Blood Vessels
Neoplasms
Growth
Genetic Promoter Regions
Small Interfering RNA
Carcinogenesis
Cell Proliferation
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells. / Kim, S. H.; Kim, E. J.; Hitomi, M.; Oh, S. Y.; Jin, X.; Jeon, H. M.; Beck, S.; Jin, X.; Kim, J. K.; Park, C. G.; Chang, S. Y.; Yin, J.; Kim, T.; Jeon, Y. J.; Song, J.; Lim, Y. C.; Lathia, J. D.; Nakano, I.; Kim, Hyunggee.

In: Cell Death and Differentiation, Vol. 22, No. 9, 11.09.2015, p. 1517-1525.

Research output: Contribution to journalArticle

Kim, SH, Kim, EJ, Hitomi, M, Oh, SY, Jin, X, Jeon, HM, Beck, S, Jin, X, Kim, JK, Park, CG, Chang, SY, Yin, J, Kim, T, Jeon, YJ, Song, J, Lim, YC, Lathia, JD, Nakano, I & Kim, H 2015, 'The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells', Cell Death and Differentiation, vol. 22, no. 9, pp. 1517-1525. https://doi.org/10.1038/cdd.2015.7
Kim, S. H. ; Kim, E. J. ; Hitomi, M. ; Oh, S. Y. ; Jin, X. ; Jeon, H. M. ; Beck, S. ; Jin, X. ; Kim, J. K. ; Park, C. G. ; Chang, S. Y. ; Yin, J. ; Kim, T. ; Jeon, Y. J. ; Song, J. ; Lim, Y. C. ; Lathia, J. D. ; Nakano, I. ; Kim, Hyunggee. / The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 9. pp. 1517-1525.
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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.",
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T1 - The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

AU - Kim, S. H.

AU - Kim, E. J.

AU - Hitomi, M.

AU - Oh, S. Y.

AU - Jin, X.

AU - Jeon, H. M.

AU - Beck, S.

AU - Jin, X.

AU - Kim, J. K.

AU - Park, C. G.

AU - Chang, S. Y.

AU - Yin, J.

AU - Kim, T.

AU - Jeon, Y. J.

AU - Song, J.

AU - Lim, Y. C.

AU - Lathia, J. D.

AU - Nakano, I.

AU - Kim, Hyunggee

PY - 2015/9/11

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N2 - 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.

AB - 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.

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