Downregulation of miR-452 promotes stem-like traits and tumorigenicity of gliomas.
Downregulation of miR-452 promotes stem-like traits and tumorigenicity of gliomas.
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miR-452 的下调促进神经胶质瘤的干样特征和致瘤性
DOI：
10.1158/1078-0432.ccr-12-3794
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发表时间：
2013-07-01
期刊：
影响因子：
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通讯作者：
Song L
中科院分区：
文献类型：
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作者：
Liu L;Chen K;Wu J;Shi L;Hu B;Cheng S;Li M;Song L
目的：据报道，在神经嵴发育过程中，神经嵴干细胞分化需要 miR-452。然而，miR-452 在神经胶质瘤中的生物学作用仍不清楚。本研究的目的是评估 miR-452 对神经胶质瘤细胞干细胞样特性和肿瘤发生的影响。实验设计：使用实时 PCR 检查神经胶质瘤细胞和神经胶质瘤组织中 miR-452 的表达。使用患者来源的神经胶质瘤细胞和神经胶质瘤细胞系在体外和体内研究了 miR-452 对干细胞样特征和肿瘤发生的影响。进行蛋白质印迹和荧光素酶报告基因检测以检查 miR-452 对 Bmi-1、LEF1 和 TCF4 的负调节。通过亚硫酸氢盐基因组测序 PCR 检查 miR-452 启动子区域的甲基化。结果：miR-452在胶质瘤细胞和临床胶质瘤组织中显着下调。 miR-452 水平与世界卫生组织 (WHO) 分级和患者生存率呈负相关。 miR-452直接靶向并抑制多种干性调节因子，包括Bmi-1、LEF1和TCF4，导致体外和体内神经胶质瘤细胞的干样特征和肿瘤发生减少。此外，我们发现神经胶质瘤中 miR-452 的下调是由其启动子区域的高甲基化引起的。结论：miR-452的下调在促进神经胶质瘤的干样特征和肿瘤发生中发挥重要作用，并可能代表该疾病的新的预后生物标志物和治疗靶点。临床癌症研究； 19（13）； 3429–38。 ©2013 AACR。
Purpose: miR-452 is reported to be required for neural crest stem cell differentiation during neural crest development. However, the biologic role of miR-452 in gliomas remains unclear. The aim of the present study was to evaluate the effect of miR-452 on the stem-like properties and tumorigenesis of glioma cells. Experimental Design: The expression of miR-452 was examined in glioma cells and glioma tissues using real-time PCR. The effects of miR-452 on stem-like traits and tumorigenesis were investigated in vitro and in vivo using patient-derived glioma cells and glioma cell lines. Western blotting and luciferase reporter assays were conducted to examine the negative regulation of Bmi-1, LEF1, and TCF4 by miR-452. The methylation of the miR-452 promoter region was examined by bisulfite genomic sequencing PCR. Results: miR-452 was markedly downregulated in glioma cells and clinical glioma tissues. miR-452 levels were inversely correlated with World Health Organization (WHO) grades and patient survival. miR-452 directly targeted and suppressed multiple stemness regulators, including Bmi-1, LEF1, and TCF4, resulting in reduced stem-like traits and tumorigenesis of glioma cells in vitro and in vivo. Furthermore, we showed that downregulation of miR-452 in gliomas was caused by hypermethylation of its promoter region. Conclusions: Downregulation of miR-452 plays an important role in promoting the stem-like traits and tumorigenesis of gliomas and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 19(13); 3429–38. ©2013 AACR.