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.

译文

:Musashi1(Msi1)是神经系统发育过程中所需的高度保守的RNA结合蛋白。 Msi1已被表征为干细胞标志物,控制着自我更新和分化之间的平衡,并且还与肿瘤发生有关,在多种肿瘤类型中高表达。我们分析了一大批髓母细胞瘤样本中的Msi1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表达水平证明是不良预后的迹象。已确定在髓母细胞瘤的分子亚组3和4中Msi1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表达可减少异种移植物中Daoy髓母细胞瘤细胞的生长。为了表征Msi1在髓母细胞瘤中的参与,我们进行了不同的高通量分析。核糖蛋白免疫沉淀后再进行微阵列分析(RIP芯片)用于鉴定优先与Daoy细胞中Msi1蛋白相关的mRNA种类。我们还使用聚类分析来鉴定与我们的髓母细胞瘤队列中的Msi1表达模式相似或相反的基因。网络研究确定RAC1,CTGF,SDCBP,SRC,PRL和SHC1是与Msi1相关的网络的主要节点。我们的结果表明,Msi1在髓母细胞瘤形成过程中起多个过程的调节作用,并可能成为重要的治疗靶点。

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