An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease.
An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease.
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DOI：
10.1101/gr.166223.113
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发表时间：
2014-02
期刊：
影响因子：
7
通讯作者：
Hunter KW
中科院分区：
文献类型：
--
作者：
Faraji F;Hu Y;Wu G;Goldberger NE;Walker RC;Zhang J;Hunter KW
转移是随机基因组和表观遗传事件导致基因表达谱驱动肿瘤播散的结果。在这里，我们利用的原则，转移倾向是由遗传背景修改，以产生预后基因表达的签名，照亮调节转移。我们还鉴定了多种microRNA，其种系变异与肿瘤进展和转移有因果关系。我们采用来自一组重组近交系小鼠的肿瘤中的全局基因表达谱的网络分析来鉴定以Cnot 2为中心的共表达基因的网络，其预测无转移生存。调节Cnot 2表达改变体内肿瘤细胞转移潜能，支持Cnot 2在转移中的功能作用。同一肿瘤组的小RNA测序显示Mir 216/217簇的表达与肿瘤进展之间呈负相关。表达数量性状基因座分析（eQTL）在Mir 216/217位点鉴定了顺式eQTL，表明表达差异可能是遗传的。Mir 216/217在肿瘤细胞中的异位表达抑制体内转移。最后，整合小RNA测序和mRNA表达谱数据，揭示miR-3470 a/B靶向高比例的网络转录物。对Mir 3470 a/B的体内分析表明，两者均促进转移。此外，Mir 3470 b可能是Cnot 2网络的调节因子，因为其过表达下调网络枢纽基因的表达并增强体内转移，表型模仿Cnot 2敲低。从这种策略得到的数据确定Cnot 2作为一种新的转移调节剂，并证明了我们的系统水平的方法在确定转移的调节剂的力量。
Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression profiles in tumors derived from a panel of recombinant inbred mice to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis-free survival. Modulating Cnot2 expression changes tumor cell metastatic potential in vivo, supporting a functional role for Cnot2 in metastasis. Small RNA sequencing of the same tumor set revealed a negative correlation between expression of the Mir216/217 cluster and tumor progression. Expression quantitative trait locus analysis (eQTL) identified cis-eQTLs at the Mir216/217 locus, indicating that differences in expression may be inherited. Ectopic expression of Mir216/217 in tumor cells suppressed metastasis in vivo. Finally, small RNA sequencing and mRNA expression profiling data were integrated to reveal that miR-3470a/b target a high proportion of network transcripts. In vivo analysis of Mir3470a/b demonstrated that both promote metastasis. Moreover, Mir3470b is a likely regulator of the Cnot2 network as its overexpression down-regulated expression of network hub genes and enhanced metastasis in vivo, phenocopying Cnot2 knockdown. The resulting data from this strategy identify Cnot2 as a novel regulator of metastasis and demonstrate the power of our systems-level approach in identifying modifiers of metastasis.
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影响因子：
11.2
作者：
Alsarraj J;Walker RC;Webster JD;Geiger TR;Crawford NP;Simpson RM;Ozato K;Hunter KW
通讯作者：
Hunter KW
miR-216b通过靶向KRAS抑制鼻咽癌中的肿瘤生长和侵袭
影响因子：
4
作者：
Deng, Min;Tang, Hailin;Li, Guiyuan
通讯作者：
Li, Guiyuan
影响因子：
6
作者：
Bao, Lili;Hazari, Sidhartha;Dash, Srikanta
通讯作者：
Dash, Srikanta
DOI：
10.1073/pnas.0601231103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Ein-Dor, L;Zuk, O;Domany, E
通讯作者：
Domany, E
影响因子：
5.3
作者：
Ezzeddine, Nader;Chang, Tsung-Cheng;Shyu, Ann-Bin
通讯作者：
Shyu, Ann-Bin