Loss of miR-204 expression enhances glioma migration and stem cell-like phenotype.
Loss of miR-204 expression enhances glioma migration and stem cell-like phenotype.
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DOI：
10.1158/0008-5472.can-12-2895
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发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Ying Z;Li Y;Wu J;Zhu X;Yang Y;Tian H;Li W;Hu B;Cheng SY;Li M
神经胶质瘤细胞和神经干细胞亚群之间的表型相似性早已被认识到。许多这些相似的特性，包括强大的自我更新，迁移和入侵能力，是胶质瘤细胞的标志，使它们具有极强的攻击性。然而，这种特征的分子机制，特别是在神经胶质瘤干细胞样细胞驱动这种疾病，仍然知之甚少。在这里，我们报告了比较神经胶质瘤细胞和神经干细胞的差异miRNA表达筛选的结果，我们发现miR-204在两种类型的细胞中显著下调。机制研究显示，miR-204通过靶向干细胞调控转录因子SOX 4和迁移促进受体EphB 2同时抑制胶质瘤细胞的自我更新、干细胞相关表型和迁移。恢复胶质瘤细胞中的miR-204表达可以抑制体内肿瘤发生和侵袭性，并增加宿主的总体生存率。进一步的评估显示，miR-204启动子是高甲基化的，减弱启动子甲基化足以上调胶质瘤细胞中的miR-204。总之，我们的发现揭示了miR-204作为恶性胶质瘤细胞中干细胞样表型和细胞运动性发展的关键调节因子。
Phenotypic similarities have long been recognized between subpopulations of glioma cells and neural stem cells. Many of these similar properties, including the robust abilities to self-renew, migrate and invade, are hallmarks of glioma cells that render them extremely aggressive. However, the molecular mechanisms underlying this character, particularly in glioma stem-like cells that drive this disease, remain poorly understood. Here we report the results of a differential miRNA expression screen that compared glioma cells and neural stem cells, where we found that miR-204 was markedly down-regulated in both types of cells. Mechanistic investigations revealed that miR-204 simultaneously suppressed self-renewal, stem cell associated phenotype and migration of glioma cells via targeting the stemness-governing transcriptional factor SOX4 and the migration-promoting receptor EphB2. Restoring miR-204 expression in glioma cells suppressed tumorigenesis and invasiveness in vivo and increased overall host survival. Further evaluation revealed that the miR-204 promoter was hypermethylated and that attenuating promoter methylation was sufficient to upregulate miR-204 in glioma cells. Together, our findings reveal miR-204 as a pivotal regulator of the development of stem cell-like phenotypes and cell motility in malignant glioma cells.