The number of titrated microRNA species dictates ceRNA regulation.
The number of titrated microRNA species dictates ceRNA regulation.
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DOI：
10.1093/nar/gky286
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发表时间：
2018-05-18
影响因子：
14.9
通讯作者：
Califano A
中科院分区：
文献类型：
--
作者：
Chiu HS;Martínez MR;Komissarova EV;Llobet-Navas D;Bansal M;Paull EO;Silva J;Yang X;Sumazin P;Califano A
microRNA（miRNAs）在癌症中起着关键作用，但它们将其靶点偶联为竞争性内源性RNA（ceRNA）的倾向最近才出现。多种模型研究了ceRNA的调控，但这些模型没有考虑到miRNA与许多靶点的共调控效应。我们对ceRNA进行了建模，并使用miRNA/mRNA相互作用动力学的既定参数模拟了其作用，同时考虑了多个miRNA与许多靶标的共调节。我们的模拟表明，许多miRNA物种的共同调节更有可能产生生理相关的上下文无关的耦合。为了验证这一点，我们研究了来自四种肿瘤背景的推断ceRNA网络的重叠-我们提出的泛癌症ceRNA相互作用组（PCI）。PCI是由基因之间的相互作用组成的，这些基因之间的相互作用是由几乎三倍于其他推断的ceRNA相互作用的miRNA共同调节的。来自表达谱数据集的证据表明，PCI相互作用可预测12种独立肿瘤和非肿瘤背景下的基因表达。生化分析证实了两个PCI子网络的ceRNA偶联，包括癌基因CCND 1、HIF 1A和HMGA 2，以及肿瘤抑制因子PTEN、RB 1和TP 53。我们的研究结果表明，PCI是丰富的上下文无关的相互作用，耦合了许多miRNA种类，更有可能是上下文无关的。
microRNAs (miRNAs) play key roles in cancer, but their propensity to couple their targets as competing endogenous RNAs (ceRNAs) has only recently emerged. Multiple models have studied ceRNA regulation, but these models did not account for the effects of co-regulation by miRNAs with many targets. We modeled ceRNA and simulated its effects using established parameters for miRNA/mRNA interaction kinetics while accounting for co-regulation by multiple miRNAs with many targets. Our simulations suggested that co-regulation by many miRNA species is more likely to produce physiologically relevant context-independent couplings. To test this, we studied the overlap of inferred ceRNA networks from four tumor contexts—our proposed pan-cancer ceRNA interactome (PCI). PCI was composed of interactions between genes that were co-regulated by nearly three-times as many miRNAs as other inferred ceRNA interactions. Evidence from expression-profiling datasets suggested that PCI interactions are predictive of gene expression in 12 independent tumor- and non-tumor contexts. Biochemical assays confirmed ceRNA couplings for two PCI subnetworks, including oncogenes CCND1, HIF1A and HMGA2, and tumor suppressors PTEN, RB1 and TP53. Our results suggest that PCI is enriched for context-independent interactions that are coupled by many miRNA species and are more likely to be context independent.
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影响因子：
4.4
作者：
Yip DK;Pang IK;Yip KY
通讯作者：
Yip KY
影响因子：
16
作者：
Bosson, Andrew D.;Zamudio, Jesse R.;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.
DOI：
10.1126/science.aad2509
发表时间：
2015-12-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Amin ND;Bai G;Klug JR;Bonanomi D;Pankratz MT;Gifford WD;Hinckley CA;Sternfeld MJ;Driscoll SP;Dominguez B;Lee KF;Jin X;Pfaff SL
通讯作者：
Pfaff SL
DOI：
10.1158/1541-7786.mcr-14-0674-t
发表时间：
2015-08
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Dorr C;Janik C;Weg M;Been RA;Bader J;Kang R;Ng B;Foran L;Landman SR;O'Sullivan MG;Steinbach M;Sarver AL;Silverstein KA;Largaespada DA;Starr TK
通讯作者：
Starr TK
影响因子：
--
作者：
Casimiro, Mathew C.;Wang, Chenguang;Pestell, Richard G.
通讯作者：
Pestell, Richard G.