Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs.
Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs.
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DOI：
10.1038/onc.2012.311
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发表时间：
2013-06-13
期刊：
影响因子：
8
通讯作者：
Stallings, R. L.
中科院分区：
文献类型：
--
作者：
Das, S.;Bryan, K.;Buckley, P. G.;Piskareva, O.;Bray, I. M.;Foley, N.;Ryan, J.;Lynch, J.;Creevey, L.;Fay, J.;Prenter, S.;Koster, J.;van Sluis, P.;Versteeg, R.;Eggert, A.;Schulte, J. H.;Schramm, A.;Mestdagh, P.;Vandesompele, J.;Speleman, F.;Stallings, R. L.
microRNA参与了许多形式的癌症的发病机制，包括儿科癌症神经母细胞瘤，但导致miRNA表达改变的潜在机制通常是未知的。在这里，一种分析DNA甲基化与miRNA和mRNA表达数据集结合的新的综合方法在神经母细胞瘤中鉴定了67种表观遗传调节的miRNA。当在肿瘤中表达不足时，这些miRNAs中的很大一部分（42%）与患者生存率低下相关。此外，我们证明了这组表观遗传沉默的miRNA以高度冗余的方式靶向了大量在存活率差的患者的肿瘤中过度表达的基因。表观遗传学调节的miRNA靶向的基因富集了许多生物学过程，包括细胞分化的调节。涉及几种表观遗传学沉默的miRNA的异位过表达的功能研究对神经母细胞瘤细胞活力具有负面影响，进一步支持这些miRNA的失活对神经母细胞瘤疾病发病机制很重要的概念。一个基因座，miR-340，诱导分化或细胞凋亡的细胞环境依赖性的方式，表明该miRNA的肿瘤抑制功能。有趣的是，已确定miR-340通过上游基因组区域的去甲基化而上调，所述去甲基化发生在由全反式视黄酸（ATRA）诱导的神经母细胞瘤细胞分化过程中。对miR-340的进一步生物学研究表明，它通过靶向其3' UTR直接抑制SOX 2转录因子，解释了SOX 2被ATRA下调的机制。虽然SOX 2有助于维持干细胞处于未分化状态，但我们证明miR-340介导的SOX 2下调不是ATRA诱导分化发生所必需的。总之，我们的研究结果证实了miRNA表观基因组的动态性质，并确定了一个显着的网络的miRNA/mRNA的相互作用，显着有助于神经母细胞瘤疾病的发病机制。
MicroRNAs contribute to the pathogenesis of many forms of cancer, including the pediatric cancer neuroblastoma, but the underlying mechanisms leading to altered miRNA expression are often unknown. Here, a novel integrated approach for analyzing DNA methylation coupled with miRNA and mRNA expression data sets identified 67 epigenetically regulated miRNA in neuroblastoma. A large proportion (42%) of these miRNAs were associated with poor patient survival when under-expressed in tumors. Moreover, we demonstrate that this panel of epigenetically silenced miRNAs targets a large set of genes that are over-expressed in tumors from patients with poor survival in a highly redundant manner. The genes targeted by the epigenetically regulated miRNAs are enriched for a number of biological processes, including regulation of cell differentiation. Functional studies involving ectopic over-expression of several of the epigenetically silenced miRNAs had a negative impact on neuroblastoma cell viability, providing further support to the concept that inactivation of these miRNAs is important for neuroblastoma disease pathogenesis. One locus, miR-340, induced either differentiation or apoptosis in a cell context dependent manner, indicating a tumor suppressive function for this miRNA. Intriguingly, it was determined that miR-340 is up-regulated by demethylation of an upstream genomic region that occurs during the process of neuroblastoma cell differentiation induced by all-trans retinoic acid (ATRA). Further biological studies of miR-340 revealed that it directly represses the SOX2 transcription factor by targeting of its 3’ UTR, explaining the mechanism by which SOX2 is down-regulated by ATRA. Although SOX2 contributes to the maintenance of stem cells in an undifferentiated state, we demonstrate that miR-340 mediated down-regulation of SOX2 is not required for ATRA induced differentiation to occur. In summary, our results exemplify the dynamic nature of the miRNA epigenome and identify a remarkable network of miRNA/mRNA interactions that significantly contribute to neuroblastoma disease pathogenesis.
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影响因子：
3.7
作者：
Corcoran DL;Pandit KV;Gordon B;Bhattacharjee A;Kaminski N;Benos PV
通讯作者：
Benos PV
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.1016/j.mrfmmm.2011.03.008
发表时间：
2011-12-01
影响因子：
2.3
作者：
Kunej, Tanja;Godnic, Irena;Calin, George Adrian
通讯作者：
Calin, George Adrian
影响因子：
3.9
作者：
Girgert, R;Schweizer, P
通讯作者：
Schweizer, P
DOI：
10.1158/1078-0432.ccr-09-3215
发表时间：
2010-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Buckley PG;Alcock L;Bryan K;Bray I;Schulte JH;Schramm A;Eggert A;Mestdagh P;De Preter K;Vandesompele J;Speleman F;Stallings RL
通讯作者：
Stallings RL