A Systematic Approach to Defining the microRNA Landscape in Metastasis
A Systematic Approach to Defining the microRNA Landscape in Metastasis
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DOI：
10.1158/0008-5472.can-15-0997
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发表时间：
2015-08-01
期刊：
影响因子：
11.2
通讯作者：
Allgayer, Heike
中科院分区：
文献类型：
--
作者：
Mudduluru, Giridhar;Abba, Mohammed;Allgayer, Heike
microRNA（miRNA）在癌症进展过程中发生变化。我们使用系统的方法定义了转移相关的miRNA景观。我们分析并验证了一系列独特的人类结直肠转移组织及其匹配的原发性肿瘤和相应的正常组织中的miRNA和mRNA表达。我们鉴定了一种在转移瘤中差异表达的独特miRNA标记。这些miRNAs中的三种被鉴定为通过许多新靶点起作用的EMT调节网络的关键驱动因素。这些靶点包括SIAH 1、SETD 2、ZEB 2，特别是FOXN 3，我们首次证明FOXN 3是N-钙粘蛋白的直接转录抑制因子。在两种不同的体内模型中，Ncadherin表达的调节对迁移、侵袭和转移有显著影响。定义网络的miRNAs的显著失调在一个独立的患者集以及来自6,000多名患者的各种恶性肿瘤数据库中得到证实。我们的数据定义了一个新的转移协调网络的基础上系统的假设生成转移组织。(C)2015年AACR。
The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of Ncadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues. (C) 2015 AACR.