The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells
The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells
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DOI：
10.1038/cdd.2015.7
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发表时间：
2015-09-01
影响因子：
12.4
通讯作者：
Kim, H.
中科院分区：
文献类型：
--
作者：
Kim, S-H;Kim, E-J;Kim, H.
胶质母细胞瘤（GBMs）维持其细胞异质性，胶质瘤干细胞（GSCs）产生多种肿瘤细胞类型。在这里，我们研究了Lim结构域2 （LMO2）在小鼠和人GBM和GSCs中的致癌作用。与分化的后代细胞相比，人患者来源的GSCs中LMO2的表达较高。体外和体内GSC的增殖都需要LMO2，因为shrna介导的LMO2沉默了源自人GSC的肿瘤生长。此外，LMO2足以诱导小鼠癌前星形胶质细胞的干细胞特征（干性），因为强迫LMO2的表达促进了Ink4a/Arf缺失小鼠衍生的星形胶质细胞的体外和体内生长以及GSC表型的获得。在体外和体内，小鼠和人的一部分GSCs转化为血管内皮样肿瘤细胞，其表型通过LMO2沉默而减弱，并通过LMO2过表达而促进。在机制上，LMO2诱导胶质瘤干细胞的作用是通过Jagged1的转录调控介导的，从而激活Notch通路，而LMO2直接占据VE-cadherin基因的启动子区域，从而获得内皮细胞表型。随后，选择性消融人gsc来源的表达ve -cadherin的细胞，减弱小鼠颅内肿瘤血管的形成，从而显著延长小鼠的生存期。临床上，LMO2在GBM组织中表达升高，与GBM患者预后呈负相关。综上所述，我们的研究结果描述了LMO2在诱导肿瘤发生和血管生成方面的双重作用，并为GBMs提供了潜在的治疗靶点。
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.