miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells.
miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells.
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miR-124和miR-137抑制多形性胶质母细胞瘤细胞的增殖并诱导脑肿瘤干细胞的分化。
DOI：
10.1186/1741-7015-6-14
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发表时间：
2008-06-24
期刊：
影响因子：
9.3
通讯作者：
Hodgson JG
中科院分区：
文献类型：
--
作者：
Silber J;Lim DA;Petritsch C;Persson AI;Maunakea AK;Yu M;Vandenberg SR;Ginzinger DG;James CD;Costello JF;Bergers G;Weiss WA;Alvarez-Buylla A;Hodgson JG
多形性胶质母细胞瘤（GBM）是一种总是致命的中枢神经系统肿瘤，尽管治疗与手术，放疗和化疗。需要进一步深入了解推动GBM形成的分子和细胞机制，以改善患者的预后。microRNA正在成为细胞分化和增殖的重要调节因子，并与多种癌症的病因学有关，但microRNA在GBM中的作用仍然知之甚少。在这项研究中，我们研究了microRNA在调节神经干细胞和胶质母细胞瘤-多形性肿瘤细胞的分化和增殖中的作用。我们使用定量RT-PCR来评估microRNA在高级别星形细胞瘤和成年小鼠神经干细胞中的表达。为了评估候选microRNA在高级星形细胞瘤中的功能，我们将miR模拟物转染到培养的小鼠神经干细胞、小鼠少突胶质细胞瘤衍生的干细胞、人多形性胶质母细胞瘤衍生的干细胞和多形性胶质母细胞瘤细胞系中。通过免疫染色评估细胞分化，并使用荧光激活细胞分选法测定细胞增殖。我们的研究显示，microRNA-124和microRNA-137的表达水平在间变性星形细胞瘤（世界卫生组织III级）和多形性胶质母细胞瘤（世界卫生组织IV级）中相对于非肿瘤性脑组织显著降低（P < 0.01），并且在生长因子撤除后培养的小鼠神经干细胞分化期间增加8至20倍。在用5-氮杂-2 '-脱氧胞苷（5-aza-dC）抑制DNA甲基化后，多形性胶质母细胞瘤细胞系U87和U251中microRNA-137的表达增加了3至12倍。microRNA-124或microRNA-137的转染诱导了与小鼠神经干细胞、源自S100β-v-erbB肿瘤的小鼠少突胶质瘤衍生干细胞和分化簇133+人多形性胶质母细胞瘤衍生干细胞（SF 6969）中的神经元分化一致的形态学变化和标志物表达。microRNA-124或microRNA-137的转染也诱导U251和SF6969多形性胶质母细胞瘤细胞中的G1细胞周期停滞，这与细胞周期蛋白依赖性激酶6和磷酸化视网膜母细胞瘤（pSer 807/811）蛋白的表达降低相关。microRNA-124和microRNA-137诱导成年小鼠神经干细胞、小鼠少突胶质细胞瘤衍生的干细胞和人多形性胶质母细胞瘤衍生的干细胞的分化，并诱导多形性胶质母细胞瘤细胞周期停滞。这些结果表明，将微小RNA-124和/或微小RNA-137靶向递送至多形性胶质母细胞瘤肿瘤细胞对于治疗这种疾病可能是治疗有效的。
Glioblastoma multiforme (GBM) is an invariably fatal central nervous system tumor despite treatment with surgery, radiation, and chemotherapy. Further insights into the molecular and cellular mechanisms that drive GBM formation are required to improve patient outcome. MicroRNAs are emerging as important regulators of cellular differentiation and proliferation, and have been implicated in the etiology of a variety of cancers, yet the role of microRNAs in GBM remains poorly understood. In this study, we investigated the role of microRNAs in regulating the differentiation and proliferation of neural stem cells and glioblastoma-multiforme tumor cells. We used quantitative RT-PCR to assess microRNA expression in high-grade astrocytomas and adult mouse neural stem cells. To assess the function of candidate microRNAs in high-grade astrocytomas, we transfected miR mimics to cultured-mouse neural stem cells, -mouse oligodendroglioma-derived stem cells, -human glioblastoma multiforme-derived stem cells and -glioblastoma multiforme cell lines. Cellular differentiation was assessed by immunostaining, and cellular proliferation was determined using fluorescence-activated cell sorting. Our studies revealed that expression levels of microRNA-124 and microRNA-137 were significantly decreased in anaplastic astrocytomas (World Health Organization grade III) and glioblastoma multiforme (World Health Organization grade IV) relative to non-neoplastic brain tissue (P < 0.01), and were increased 8- to 20-fold during differentiation of cultured mouse neural stem cells following growth factor withdrawal. Expression of microRNA-137 was increased 3- to 12-fold in glioblastoma multiforme cell lines U87 and U251 following inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5-aza-dC). Transfection of microRNA-124 or microRNA-137 induced morphological changes and marker expressions consistent with neuronal differentiation in mouse neural stem cells, mouse oligodendroglioma-derived stem cells derived from S100β-v-erbB tumors and cluster of differentiation 133+ human glioblastoma multiforme-derived stem cells (SF6969). Transfection of microRNA-124 or microRNA-137 also induced G1 cell cycle arrest in U251 and SF6969 glioblastoma multiforme cells, which was associated with decreased expression of cyclin-dependent kinase 6 and phosphorylated retinoblastoma (pSer 807/811) proteins. microRNA-124 and microRNA-137 induce differentiation of adult mouse neural stem cells, mouse oligodendroglioma-derived stem cells and human glioblastoma multiforme-derived stem cells and induce glioblastoma multiforme cell cycle arrest. These results suggest that targeted delivery of microRNA-124 and/or microRNA-137 to glioblastoma multiforme tumor cells may be therapeutically efficacious for the treatment of this disease.
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