A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways.
A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways.
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DOI：
10.1038/ncomms12885
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发表时间：
2016-10-04
影响因子：
16.6
通讯作者：
Cheng, Shi-Yuan
中科院分区：
文献类型：
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作者：
Huang, Tianzhi;Alvarez, Angel A.;Pangeni, Rajendra P.;Horbinski, Craig M.;Lu, Songjian;Kim, Sung-Hak;James, C. David;Raizer, Jeffery J.;Kessler, John A.;Brenann, Cameron W.;Sulman, Erik P.;Finocchiaro, Gaetano;Tan, Ming;Nishikawa, Ryo;Lu, Xinghua;Nakano, Ichiro;Hu, Bo;Cheng, Shi-Yuan
分子定义的亚分类与恶性胶质母细胞瘤（GBM）的表型相关。然而，目前对GBM复发中经常涉及的亚类转换的分子基础的理解充其量仍然是初步的。在这里，我们报告了在前神经（PN）中有活性但在间充质（MES）GBM中无活性的典型Wnt信号传导，沿着与MES GBM相比在PN中以高水平表达的miR-125 b和miR-20 b，组成了涉及TCF 4-miR-125 b/miR-20 b-FZD 6的调控回路。FZD 6通过激活CaMKII-TAK 1-NLK信号传导，从而减弱Wnt通路活性，同时促进STAT 3和NF-κB信号传导，而这些信号传导是MES相关表型的重要调节因子，从而充当该回路的负调节因子。这些发现通过靶向PN与MES GBM中的差异富集途径得到证实，该途径导致不同GBM亚型的抑制。该回路各成分的相关表达与临床GBM的预后有关。我们的研究结果为了解GBM的发病机制和改善GBM的治疗提供了见解。 胶质母细胞瘤（GBM）分为前神经性（PN）、神经间质性（MES）和经典GBM。在这里，作者表明，Wnt信号传导，miR-125 b和miR-20 b建立了一个包括FZD 6的调节电路，该电路将PN与MES亚型区分开来。
Molecularly defined subclassification is associated with phenotypic malignancy of glioblastoma (GBM). However, current understanding of the molecular basis of subclass conversion that is often involved in GBM recurrence remain rudimentary at best. Here we report that canonical Wnt signalling that is active in proneural (PN) but inactive in mesenchymal (MES) GBM, along with miR-125b and miR-20b that are expressed at high levels in PN compared with MES GBM, comprise a regulatory circuit involving TCF4-miR-125b/miR-20b-FZD6. FZD6 acts as a negative regulator of this circuit by activating CaMKII–TAK1–NLK signalling, which, in turn, attenuates Wnt pathway activity while promoting STAT3 and NF-κB signalling that are important regulators of the MES-associated phenotype. These findings are confirmed by targeting differentially enriched pathways in PN versus MES GBM that results in inhibition of distinct GBM subtypes. Correlative expressions of the components of this circuit are prognostic relevant for clinical GBM. Our findings provide insights for understanding GBM pathogenesis and for improving treatment of GBM. Glioblastoma (GBM) is classified as proneural (PN), neural, mesenchymal (MES) and classical GBM. Here the authors show that Wnt signalling, miR-125b and miR-20b establish a regulatory circuitry including FZD6 which distinguishes PN from the MES subtype.
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影响因子：
11.2
作者：
Horst D;Chen J;Morikawa T;Ogino S;Kirchner T;Shivdasani RA
通讯作者：
Shivdasani RA
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作者：
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通讯作者：
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作者：
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通讯作者：
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作者：
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