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Novel mechanisms of microRNA-mediated regulation of key TGFbeta effector CTGF in glioblastoma multiforme.

机译:microRNA介导的胶质母细胞瘤中关键TGFbeta效应子CTGF调控的新机制。

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摘要

The TGFbeta signaling pathway is known to directly induce transcription of connective tissue growth factor (CTGF, CCN2) with profound and complex consequences in human cancers. While TGFbeta and CTGF have varying and often conflicting roles in tumorigenesis, depending on cell context, both are thought to enhance malignancy of the brain cancer glioblastoma multiforme (GBM). We and others have previously reported that the effects of TGFbeta pathway activation can be abrogated via regulation of multiple components by the classically oncogenic microRNA cluster miR-17∼92. Described herein, we have discovered two novel mechanisms, both dependent on the TGFbeta pathway, whereby microRNAs modulate CTGF in GBM. In the first study, we demonstrate that miR-18a, a member of the miR-17~92 cluster, inhibits CTGF both directly and indirectly. The latter is achieved via targeting of Smad3, a vital component of the TGFbeta pathway. The result is profound downregulation of CTGF at the mRNA and protein levels. Additionally, we discovered an anti-correlation between expression of miR-18 and TGFbeta target genes in primary GBM, which has significant implications in patient survival. This surprising result suggests the classical "oncomiR", miR-17~92, instead functions as a tumor suppressor in GBM. In the second study, we demonstrate that miR-133 regulates CTGF directly, but is only expressed in the absence of TGFbeta signaling. Thus, miR-133 augments the effects of TGFbeta on CTGF expression by inhibiting CTGF only when TGFbeta signaling is inactive. In contrast, miR-133-mediated repression of CTGF is alleviated when TGFbeta signaling is active. The effective result is TGFbeta-dependent post-transcriptional modification of CTGF expression and sustained induction of CTGF. While we discovered these novel mechanisms of microRNA-mediated regulation in the context of a human GBM cell line, similar axes of regulation may be important in other cell types with alternative microRNAs, pathways, and gene targets. Overall, the data presented herein highlight the complexity of microRNA function and importance of cell context.
机译:已知TGFbeta信号通路直接诱导结缔组织生长因子(CTGF,CCN2)的转录,对人类癌症产生深远而复杂的后果。尽管TGFbeta和CTGF在肿瘤发生中具有不同且经常相互冲突的作用,但取决于细胞环境,它们都被认为可增强多形性脑癌胶质母细胞瘤(GBM)的恶性程度。我们和其他人以前已经报道过,通过经典致癌的微小RNA簇miR-17〜92对多种成分的调节可以消除TGFβ途径激活的影响。本文所述,我们发现了两种新颖的机制,均依赖于TGFbeta途径,由此microRNA调节GBM中的CTGF。在第一个研究中,我们证明了miR-17〜92簇的成员miR-18a直接或间接抑制CTGF。后者是通过靶向Smad3(TGFbeta途径的重要组成部分)来实现的。结果是CTGF在mRNA和蛋白质水平上都大大下调。此外,我们发现原发性GBM中miR-18和TGFbeta靶基因的表达之间存在反相关关系,这对患者的生存具有重要意义。这一令人惊讶的结果表明,经典的“ oncomiR” miR-17〜92在GBM中起着抑癌作用。在第二项研究中,我们证明了miR-133直接调节CTGF​​,但仅在不存在TGFbeta信号的情况下表达。因此,miR-133仅在TGFbeta信号不活跃时才通过抑制CTGF来增强TGFbeta对CTGF表达的作用。相反,当TGFbeta信号激活时,miR-133介导的CTGF抑制被缓解。有效的结果是CTGF表达的TGFbeta依赖性转录后修饰和CTGF的持续诱导。尽管我们在人GBM细胞系的背景下发现了这些新的microRNA介导调控机制,但相似的调控轴在其他具有替代microRNA,途径和基因靶点的细胞类型中可能很重要。总体而言,本文提供的数据突出了microRNA功能的复杂性和细胞背景的重要性。

著录项

  • 作者

    Fox, Jamie L.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 144 p.
  • 总页数 144
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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