Integrated MicroRNA Network Analyses Identify a Poor-Prognosis Subtype of Gastric Cancer Characterized by the miR-200 Family
Integrated MicroRNA Network Analyses Identify a Poor-Prognosis Subtype of Gastric Cancer Characterized by the miR-200 Family
复制标题
整合的 microRNA 网络分析确定了以 miR-200 家族为特征的预后不良的胃癌亚型
DOI：
10.1158/1078-0432.ccr-13-1844
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发表时间：
2014-02-15
影响因子：
11.5
通讯作者：
Chen, Kexin
中科院分区：
文献类型：
--
作者：
Song, Fengju;Yang, Da;Chen, Kexin
目的：探讨microRNA能否预测胃癌患者的临床预后。我们采用microRNA和mRNA表达谱的综合分析来识别胃癌microRNA亚型及其潜在的调控情景。实验设计：通过对90例胃癌组织的microRNA谱进行一致性聚类分析来识别基于microRNA的胃癌亚型。通过基因表达谱鉴定亚型中的激活途径。进行了进一步的综合分析，以模拟每个亚型的microRNA调控网络。分别通过RT-PCR和组织芯片分析385例胃癌病例（包括90例用于分析的病例）的RNA和蛋白质表达，以验证网络中的关键microRNA和靶标。结果：90例胃癌患者的microRNA谱中发现了两种与生存率显著相关的microRNA亚型。预后不良的胃癌microRNA亚型的特征在于上皮-间质转化（EMT）标志物的过表达。这种胃癌“间充质亚型”在包括385例病例的患者队列中得到进一步验证。综合分析确定了可能驱动胃癌间充质亚型的关键microRNA调控网络。三种针对网络中大多数基因的microRNA（miR-200 c，miR-200 b和miR-125 b）与生存显著相关。功能实验表明，miR-200 b抑制ZEB 1，增强E-cadherin，抑制细胞迁移，并抑制肿瘤生长的小鼠model.Conclusions：我们已经发现了一个关键的microRNA调控网络，定义间充质胃癌亚型显着相关的胃癌总生存率差。（C）2013年AACR。
Purpose: Our aim was to investigate whether microRNAs can predict the clinical outcome of patients with gastric cancer. We used integrated analysis of microRNA and mRNA expression profiles to identify gastric cancer microRNA subtypes and their underlying regulatory scenarios.Experimental Design: MicroRNA-based gastric cancer subtypes were identified by consensus clustering analysis of microRNA profiles of 90 gastric cancer tissues. Activated pathways in the subtypes were identified by gene expression profiles. Further integrated analysis was conducted to model a microRNA regulatory network for each subtype. RNA and protein expression were analyzed by RT-PCR and tissue microarray, respectively, in a cohort of 385 gastric cancer cases (including the 90 cases for profiling) to validate the key microRNAs and targets in the network. Both in vitro and in vivo experiments were carried out to further validate the findings.Results: MicroRNA profiles of 90 gastric cancer cases identified two microRNA subtypes significantly associated with survival. The poor-prognosis gastric cancer microRNA subtype was characterized by overexpression of epithelial-to-mesenchymal transition (EMT) markers. This gastric cancer "mesenchymal subtype" was further validated in a patient cohort comprising 385 cases. Integrated analysis identified a key microRNA regulatory network likely driving the gastric cancer mesenchymal subtype. Three of the microRNAs (miR-200c, miR-200b, and miR-125b) targeting the most genes in the network were significantly associated with survival. Functional experiments demonstrated that miR-200b suppressed ZEB1, augmented E-cadherin, inhibited cell migration, and suppressed tumor growth in a mouse model.Conclusions: We have uncovered a key microRNA regulatory network that defines the mesenchymal gastric cancer subtype significantly associated with poor overall survival in gastric cancer. (C)2013 AACR.