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.

LMO2 attenuates tumor growth by targeting the Wnt signaling pathway in breast and colorectal cancer

“…The oncogenic role of LMO2 was also supported by studies in glioblastoma28 and prostate carcinoma11. However, in recent years several reports have suggested that LMO2 is a biomarker for good prognosis in DLBCL293031, acute B-lymphocytic leukemia32, and pancreatic carcinoma12, suggesting that LMO2 could also function as a tumor suppressor.…”

LIM-Only Protein 4 (LMO4) and LIM Domain Binding Protein 1 (LDB1) Promote Growth and Metastasis of Human Head and Neck Cancer (LMO4 and LDB1 in Head and Neck Cancer)

“…A function in tumor angiogenesis had not been previously described, however, and while LMO2 has been implicated in physiologic [60] and pathologic [44, 61, 62] angiogenesis, these studies provide the first evidence for LMO4 involvement in this process. This may have relevance to other epithelial malignancies in which this LIM-only protein is overexpressed, in particular carcinoma of the breast.…”

“…While these studies add to a considerable literature demonstrating that LMO and associated LIM domain binding proteins can be pro-oncogenic [5, 13, 16, 44], less is known about the involvement or function of SSBPs in cancer. Although increased SSBP2 expression was associated with shorter survival in glioblastoma [45], SSBP2 was also shown to inhibit the growth of prostate cancer cells [46] and to act as a tumor suppressor in myeloid leukemias [21].…”

Molecular mechanisms of regulation of sphingosine kinase 1

“…Additionally, LMO2 has been shown to promote angiogenic traits in glioma stem cells [23]. It has been shown in zebrafish, that knockdown of Lmo2 , via morpholino, resulted in defective intersegmental vessels [24].…”