De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures
De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures
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DOI：
10.1038/onc.2010.83
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发表时间：
2010-06-01
期刊：
影响因子：
8
通讯作者：
Radlwimmer, B.
中科院分区：
文献类型：
--
作者：
Ernst, A.;Campos, B.;Radlwimmer, B.
全反式视黄酸是细胞分化过程的有效促进剂，用于癌症治疗。胶质母细胞瘤球体培养物富含肿瘤起始细胞，并提供了体外测试新治疗方案的模型。我们研究了在此类培养物中暴露于促进分化条件的反应的分子机制。对五个独立培养物的微阵列分析表明，诱导分化后，转化生长因子β/骨形态发生蛋白、Wnt/β-连环蛋白和IGF信号传导的抑制剂上调，而几种microRNA的表达下降，特别是miR-17-92簇的表达下降。在原发性星形细胞胶质瘤（n = 82）中，miR-17-92的几个成员的表达显着高于正常脑（n = 8），并且随着肿瘤分级进展而显着增加（P < 0.05）。在一份胶质母细胞瘤样本中检测到 miR-17-92 基因座的高水平扩增。转染 miR-17-92 抑制剂可诱导胶质母细胞瘤球体细胞凋亡增加并减少细胞增殖。 Mir-17-92 抑制还与 CDKN1A、E2F1、PTEN 和 CTGF 的信使 RNA (mRNA) 和/或蛋白质表达增加相关。通过荧光素酶报告基因检测，CTGF 基因被证明是胶质母细胞瘤球体中 miR-17-92 的靶标。我们的结果表明，miR-17-92 及其靶标 CTGF 通过多种调控途径介导胶质母细胞瘤细胞的促分化治疗效果。癌基因 (2010) 29, 3411-3422; doi：10.1038/onc.2010.83； 2010 年 3 月 22 日在线发布
All-trans retinoic acid is a potent promoter of cellular differentiation processes, which is used in cancer therapy. Glioblastoma spheroid cultures are enriched in tumor-initiating cells, and provide a model to test new treatment options in vitro. We investigated the molecular mechanisms of response to exposure to differentiation-promoting conditions in such cultures. Microarray analyses of five independent cultures showed that after induction of differentiation, inhibitors of transforming growth factor beta/bone morphogenetic protein, Wnt/beta-catenin and IGF signaling were upregulated, whereas expression of several microRNAs decreased, particularly that of the miR-17-92 cluster. In primary astrocytic gliomas (n = 82), expression of several members of miR-17-92 was significantly higher relative to those of normal brain (n = 8) and significantly increased with tumor grade progression (P < 0.05). A high-level amplification of the miR-17-92 locus was detected in one glioblastoma specimen. Transfection of inhibitors of miR-17-92 induced increased apoptosis and decreased cell proliferation in glioblastoma spheroids. Mir-17-92 inhibition was also associated with increased messenger RNA (mRNA) and/or protein expression of CDKN1A, E2F1, PTEN and CTGF. The CTGF gene was shown to be a target of miR-17-92 in glioblastoma spheroids by luciferase reporter assays. Our results suggest that miR-17-92 and its target CTGF mediate effects of differentiation-promoting treatment on glioblastoma cells through multiple regulatory pathways. Oncogene (2010) 29, 3411-3422; doi:10.1038/onc.2010.83; published online 22 March 2010