The RNA-Binding Protein Musashi1 Affects Medulloblastoma Growth via a Network of Cancer-Related Genes and Is an Indicator of Poor Prognosis
The RNA-Binding Protein Musashi1 Affects Medulloblastoma Growth via a Network of Cancer-Related Genes and Is an Indicator of Poor Prognosis
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DOI：
10.1016/j.ajpath.2012.07.031
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发表时间：
2012-11-01
影响因子：
6
通讯作者：
Penalva, Luiz O. F.
中科院分区：
文献类型：
--
作者：
Vo, Dat T.;Subramaniam, Dharmalingam;Penalva, Luiz O. F.
Musashi1 （Msi1）是一种高度保守的rna结合蛋白，在神经系统发育过程中是必需的。Msi1被认为是一种干细胞标志物，控制着自我更新和分化之间的平衡，也与肿瘤发生有关，在多种肿瘤类型中高度表达。我们分析了Msi1在一大群髓母细胞瘤样本中的表达，发现与正常小脑相比，Msi1在肿瘤组织中高表达。值得注意的是，高Msi1表达水平被证明是预后不良的标志。Msi1在成神经管细胞瘤的分子亚群3和4中表达特别高。我们确定Msi1是肿瘤发生所必需的，因为通过小干扰rna抑制Msi1的表达可以减少异种移植物中道氏髓母细胞瘤细胞的生长。为了描述Msi1在成神经管细胞瘤中的作用，我们进行了不同的高通量分析。采用核糖核蛋白免疫沉淀-微阵列分析（RIP-chip）技术鉴定了day细胞中与Msi1蛋白优先相关的mRNA种类。我们还使用聚类分析来鉴定髓母细胞瘤队列中与Msi1表达模式相似或相反的基因。一项网络研究发现，RAC1、CTGF、SDCBP、SRC、PRL和SHC1是msi1相关网络的主要节点。我们的研究结果表明，Msi1在成神经管细胞瘤形成的多个过程中起调节作用，可能成为一个重要的治疗靶点。[J] .中华病理学杂志，2012,18:1762-1772;http://dx。doi.org/10.1016/j.ajpath.2012.07.031)
Musashi1 (Msi1) is a highly conserved RNA-binding protein that is required during the development of the nervous system. Msi1 has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation, and has also been implicated in tumorigenesis, being highly expressed in multiple tumor types. We analyzed Msi1 expression in a large cohort of medulloblastoma samples and found that Msi1 is highly expressed in tumor tissue compared with normal cerebellum. Notably, high Msi1 expression levels proved to be a sign of poor prognosis. Msi1 expression was determined to be particularly high in molecular subgroups 3 and 4 of medulloblastoma. We determined that Msi1 is required for tumorigenesis because inhibition of Msi1 expression by small-interfering RNAs reduced the growth of Daoy medulloblastoma cells in xenografts. To characterize the participation of Msi1 in medulloblastoma, we conducted different high-throughput analyses. Ribonucleoprotein immunoprecipitation followed by microarray analysis (RIP-chip) was used to identify mRNA species preferentially associated with Msi1 protein in Daoy cells. We also used cluster analysis to identify genes with similar or opposite expression patterns to Msi1 in our medulloblastoma cohort. A network study identified RAC1, CTGF, SDCBP, SRC, PRL, and SHC1 as major nodes of an Msi1-associated network. Our results suggest that Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target. (Am J Pathol 2012, 181:1762-1772; http://dx. doi.org/10.1016/j.ajpath.2012.07.031)