MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
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DOI：
10.1038/cddis.2012.134
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发表时间：
2012-10-04
影响因子：
9
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中科院分区：
文献类型：
--
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多形性胶质母细胞瘤（GBM）是一种异质性疾病，尽管其看似统一的病理。癌症基因组图谱的GBM基因表达数据的解卷积揭示了离散GBM亚型的不同基因表达特征的存在。最近相互矛盾的研究结果表明，microRNA（miRNA）-10b专门调节胶质瘤的生长或侵袭，而不是两者兼而有之。我们发现，在类似GBM间充质亚型的神经胶质瘤细胞系中，通过杆状病毒诱饵载体沉默miRNA-10 b可降低其生长、侵袭和血管生成，同时促进体外细胞凋亡。在原位人脑胶质瘤小鼠模型中，抑制miRNA-10 b减少了脑中间充质亚型样胶质瘤细胞的侵袭性、血管生成性和生长，并显著延长了荷胶质瘤小鼠的存活期。我们证明了miRNA-10 b的多效性是由于其抑制多种肿瘤抑制因子，包括TP 53，FOXO 3，CYLD，PAX 6，PTCH 1，HOXD 10和NOTCH 1。特别是，siRNA介导的敲除实验确定TP 53，PAX 6，NOTCH 1和HOXD 10作为我们的间充质亚型样胶质瘤细胞中的侵袭调节基因。通过询问伦勃朗，我们注意到miRNA-10 b的许多直接靶点的失调与患者生存率显著降低相关。因此，我们的研究揭示了miRNA-10 b在调节血管生成中的新作用，并表明miRNA-10 b可能是胶质瘤发生的多效性调节因子。
Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.
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影响因子：
3.7
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
通讯作者：
Holland E
影响因子：
5.7
作者：
Chai, Guolin;Liu, Ning;Yu, Xijie
通讯作者：
Yu, Xijie
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
5.3
作者：
Delpuech, Oona;Griffiths, Beatrice;Schulze, Almut
通讯作者：
Schulze, Almut
影响因子：
6
作者：
Kimura, Tokuhiro;Okada, Aiko;Okada, Yasunori
通讯作者：
Okada, Yasunori