miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis.
miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis.
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DOI：
10.18632/oncotarget.205
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Würdinger T
中科院分区：
文献类型：
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作者：
Smits M;Nilsson J;Mir SE;van der Stoop PM;Hulleman E;Niers JM;de Witt Hamer PC;Marquez VE;Cloos J;Krichevsky AM;Noske DP;Tannous BA;Würdinger T
胶质母细胞瘤（GBM）是一种预后不良的恶性脑肿瘤。GBM患者的中位生存期不到2年。GBM的特征在于快速细胞增殖、浸润性迁移和诱导血管生成。microRNA和多梳组（polycomb group，PcG）蛋白已成为基因表达的重要调控因子。在这里，我们确定miR-101在GBM中下调，导致miR-101靶PcG蛋白EZH 2的过表达，EZH 2是一种以表观遗传方式影响基因表达谱的组蛋白甲基转移酶。结果如下：通过pre-miR-101、EZH 2 siRNA或小分子DZNep在体外抑制EZH 2减弱GBM细胞生长、迁移/侵袭和GBM诱导的内皮小管形成。此外，对于每个生物过程，我们识别了与EZH 2表达显着相关的本体相关转录本。在U87-Fluc-mCherry GBM异种移植小鼠成像模型中通过全身性DZNep施用体内抑制EZH 2导致肿瘤生长减少。我们的研究结果表明EZH 2在GBM进展中具有多功能，并且其过表达至少部分是由于miR-101表达减少。抑制EZH 2可能是靶向GBM增殖、迁移和血管生成的潜在治疗策略。
Glioblastoma (GBM) is a malignant brain tumor with dismal prognosis. GBM patients have a median survival of less than 2 years. GBM is characterized by fast cell proliferation, infiltrative migration, and by the induction of angiogenesis. MicroRNAs and polycomb group (PcG) proteins have emerged as important regulators of gene expression. Here we determined that miR-101 is down-regulated in GBM, resulting in overexpression of the miR-101 target PcG protein EZH2, a histone methyltransferase affecting gene expression profiles in an epigenetic manner. Results: Inhibition of EZH2 in vitro by pre-miR-101, EZH2 siRNA, or small molecule DZNep, attenuated GBM cell growth, migration/invasion, and GBM-induced endothelial tubule formation. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Inhibition of EZH2 in vivo by systemic DZNep administration in a U87-Fluc-mCherry GBM xenograft mouse imaging model resulted in reduced tumor growth. Our results indicate that EZH2 has a versatile function in GBM progression and that its overexpression is at least partly due to decreased miR-101 expression. Inhibition of EZH2 may be a potential therapeutic strategy to target GBM proliferation, migration, and angiogenesis.