miR-29b attenuates tumorigenicity and stemness maintenance in human glioblastoma multiforme by directly targeting BCL2L2.
miR-29b attenuates tumorigenicity and stemness maintenance in human glioblastoma multiforme by directly targeting BCL2L2.
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DOI：
10.18632/oncotarget.4384
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发表时间：
2015-07-30
期刊：
影响因子：
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通讯作者：
Bae IH
中科院分区：
文献类型：
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作者：
Chung HJ;Choi YE;Kim ES;Han YH;Park MJ;Bae IH
多形性胶质母细胞瘤(GBM)是最常见的恶性脑肿瘤，具有侵袭性和侵袭性。我们先前通过miRNA微阵列分析鉴定了四个在电离辐射处理后GBM表达增强的miRNAs-miR-29b、494、193a-3p和30e-。在这项研究中，我们发现只有miR-29b通过磷酸化Akt/β-catenin信号降低基质金属蛋白酶-2活性来抑制肿瘤细胞的迁移和侵袭，并刺激更多的上皮样形态。此外，miR-29b通过抑制GBM细胞的血管形成、血管内皮生长因子和Ang-2的表达以及干性维持而抑制血管生成，表现为减少神经球的形成和肿瘤干细胞标志物蛋白的表达。这些发现支持miR-29b在人GBM细胞中的抗肿瘤特性。此外，miR-29b的表达与BCL2L2的mRNA或蛋白在不同类型的癌细胞中的表达呈负相关。有趣的是，BCL2L2mRNA在间叶型GBM中高表达。为了进一步阐明miR-29b与BCL2L2在GBM中的关系，我们进行了共转染报告实验，确定miR-29b通过直接结合其3‘UTR而下调BCL2L2的表达。最后，我们通过功能分析来检测细胞的迁移、侵袭、血管生成和干细胞特性，证实了BCL2L2抑制对miR-29b的抗肿瘤活性具有核心重要性。根据这些数据，我们认为miR-29b可能是治疗GBM的有用的治疗剂。
Glioblastoma multiforme (GBM) is the most common malignant brain tumor and exhibits aggressive and invasive behavior. We previously identified four miRNAs—miR-29b, 494, 193a-3p, and 30e—with enhanced expression in GBM following treatment of ionizing radiation by miRNA microarray analysis. In this study, we found that only miR-29b inhibited tumor cell migration and invasion by reducing MMP-2 activity via phospho-AKT/β-catenin signaling, and stimulated a more epithelial-like morphology. Moreover, miR-29b inhibits angiogenesis by attenuating tube formation and the expression of VEGF and Ang-2, and stemness maintenance in GBM cells, as demonstrated by decreasing neurosphere formation and cancer stem cell marker protein expression. These findings support the anti-tumor properties of miR-29b in human GBM cells. Furthermore, miR-29b expression was inversely proportional to that of BCL2L2 mRNA or protein in various cancer cell types. Interestingly, BCL2L2 mRNA is highly expressed in the mesenchymal type of GBM. To further elucidate the relationship between miR-29b and BCL2L2 in GBM, we performed co-transfection reporter assays and determined that miR-29b downregulates BCL2L2 expression by directly binding its 3′UTR. Finally, we confirmed that BCL2L2 repression is of central importance to miR-29b anti-tumor activity using functional assays to examine cell migration, invasion, angiogenesis, and stemness. From these data, we propose that miR-29b may be a useful therapeutic agent in GBM.