竞争性内源RNA的生物学功能及其调控

最新研究表明,RNA之间可以通过竞争结合共同的microRNA反应元件(microRNA response element, MRE)实现相互调节,这种调控模式构成竞争性内源RNA(Competing endogenous RNA, ceRNA)。已发现的ceRNA包括蛋白编码mRNA和非编码RNA,其中后者包括假基因转录物、长链非编码RNA(Long non-coding RNA, lncRNA)、环状RNA(Circular RNA, circRNA)等。文章主要从ceRNA分类的角度,阐述各类ceRNA构成的调控网络发挥的生物学功能在病理和生理相关过程中的作用,以及可能影响ceRNA调控有效性的因素。     

Integrated analysis of a competing endogenous RNA network reveals key long noncoding RNAs as potential prognostic biomarkers for hepatocellular carcinoma

Growing evidence has revealed that long noncoding RNAs (lncRNAs) have an important impact on tumorigenesis and tumor progression via a mechanism involving competing endogenous RNAs (ceRNAs). However, their use in predicting the survival of a patient with hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to develop a novel lncRNA expression–based risk score system to accurately predict the survival of patients with HCC. In our study, using expression profiles downloaded from The Cancer Genome Atlas database, the differentially expressed messenger RNAs (mRNAs), lncRNAs, and microRNAs (miRNAs) were explored in patients with HCC and normal liver tissues, and then a ceRNA network constructed. A risk score system was established between lncRNA expression of the ceRNA network and overall survival (OS) or recurrence-free survival (RFS); it was further analyzed for associations with the clinical features of patients with HCC. In HCC, 473 differentially expressed lncRNAs, 63 differentially expressed miRNAs, and 1417 differentially expressed mRNAs were detected. The ceRNA network comprised 41 lncRNA nodes, 12 miRNA nodes, 24 mRNA nodes, and 172 edges. The lncRNA expression–based risk score system for OS was constructed based on six lncRNAs (MYLK-AS1, AL359878.1, PART1, TSPEAR-AS1, C10orf91, and LINC00501), while the risk score system for RFS was based on four lncRNAs (WARS2-IT1, AL359878.1, AL357060.1, and PART1). Univariate and multivariate Cox analyses showed the risk score systems for OS or RFS were significant independent factors adjusted for clinical factors. Receiver operating characteristic curve analysis showed the area under the curve for the risk score system was 0.704 for OS, and 0.71 for RFS. Our result revealed a lncRNA expression–based risk score system for OS or RFS can effectively predict the survival of patients with HCC and aid in good clinical decision-making.     

Genome-wide data mining to construct a competing endogenous RNA network and reveal the pivotal therapeutic targets of Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative movement disorders, for which there has been no effective treatments. To clarify the pathogenesis of PD, we constructed a competing endogenous RNA (ceRNA) network based on the genome-wide RNA sequencing data. It was found that 92 RNAs were differentially expressed, including 50 mRNAs, 25 miRNAs and 17 lncRNAs, based on which a ceRNA network was constructed and evaluated from 4 aspects of number of nodes, topological coefficients, closeness centrality and betweenness centrality. The functional annotation and enrichment analysis suggested that 6 functional modules, particularly the peripheral nervous system development and toxin metabolic process, dominated the development of PD. To validate the assumption, the gene set enrichment analysis (GSEA) was conducted basing on the genome-wide RNAs regardless whether they were differentially expressed or not. Consistently, the results revealed that dysregulation of MAG, HOXB3, MYRF and PLP1 led to metabolic disorders of sphingolipid and glutathione, which contributed to the pathogenesis of PD. Also, in-depth mining of previous literature confirmed a pivotal role of these dysregulated RNAs, which had been indicated to be potential diagnostic and therapeutic biomarkers of PD. Overall, we constructed a ceRNA network based on the dysregulated mRNAs, lncRNAs and miRNAs in PD, and the aberrant expression of MAG, HOXB3, MYRF and PLP1 caused metabolism disorder of sphingolipid and glutathione, and these genes are of great significance for the diagnosis and treatment of PD.     

环状RNA: 新型生物标记物与治疗靶点

环状RNA(circular RNAs,circ RNAs)是一类在真核细胞中广泛存在的非编码RNA,具有结构稳定、丰度高及细胞或组织特异性表达等特征,可能通过多种作用方式参与基因表达调控.例如,有些circ RNA富含微小RNA(mi RNAs)结合位点,可充当竞争性内源RNA(ce RNA)结合mi RNA并阻断其对靶基因表达的抑制作用.自2013年以来,circ RNA逐渐成为RNA领域的研究热点并得到广泛关注.最新研究表明,circ RNA的表达及作用与多种疾病的发生发展、生物组织发育及细胞衰老等相关.circ RNA在不同生物样本中的表达差异使其可能成为用于疾病诊断、组织发育鉴定等方面理想的生物标记物,其在疾病中作用方式的逐步阐明,使之具有成为有效治疗靶点的潜力.circ RNA数据库的构建、预测工具的开发及对其作用方式的更深入研究,必将使之具有更广阔的应用前景.     

Prediction of a competing endogenous RNA co‐expression network as a prognostic marker in glioblastoma

Due to its high proliferation capacity and rapid intracranial spread, glioblastoma (GBM) has become one of the least curable malignant cancers. Recently, the competing endogenous RNAs (ceRNAs) hypothesis has become a focus in the researches of molecular biological mechanisms of cancer occurrence and progression. However, there is a lack of correlation studies on GBM, as well as a lack of comprehensive analyses of GBM molecular mechanisms based on high‐throughput sequencing and large‐scale sample sizes. We obtained RNA‐seq data from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression (GTEx) databases. Further, differentially expressed mRNAs were identified from normal brain tissue and GBM tissue. The similarities between the mRNA modules with clinical traits were subjected to weighted correlation network analysis (WGCNA). With the mRNAs from clinical‐related modules, a survival model was constructed by univariate and multivariate Cox proportional hazard regression analyses. Thereafter, we carried out Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, we predicted interactions between lncRNAs, miRNAs and mRNAs by TargetScan, miRDB, miRTarBase and starBase. We identified 2 lncRNAs (NORAD, XIST), 5 miRNAs (hsa‐miR‐3613, hsa‐miR‐371, hsa‐miR‐373, hsa‐miR‐32, hsa‐miR‐92) and 2 mRNAs (LYZ, PIK3AP1) for the construction of a ceRNA network, which might act as a prognostic biomarker of GBM. Combined with previous studies and our enrichment analysis results, we hypothesized that this ceRNA network affects immune activities and tumour microenvironment variations. Our research provides novel aspects to study GBM development and treatment.     

Genome-wide identification of a competing endogenous RNA network in cholangiocarcinoma

Cholangiocarcinoma (CCA) is the second widespread liver tumor with relatively poor survival. Increasing evidence in recent studies showed long noncoding RNAs (lncRNAs) exert a crucial impact on the development and progression of CCA based on the mechanism of competing endogenous RNAs (ceRNAs). However, functional roles and regulatory mechanisms of lncRNA-regulated ceRNA in CCA, are only partially understood. The expression profile of messenger RNAs (mRNAs), lncRNAs, and microRNAs (miRNAs) downloaded from The Cancer Genome Atlas were comprehensively investigated. Differential expression of these three types of RNA between CCA and corresponding precancerous tissues were screened out for further analysis. On the basis of interactive information generated from miRDB, miRTarBase, TargetScan, and miRcode public databases, we then constructed an mRNA-miRNA-lncRNA regulatory network. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were conducted to identify the biological function of the ceRNA network involved in CCA. As a result, 2883 mRNAs, 136 miRNAs, and 993 lncRNAs were screened out as differentially expressed RNAs in CCA. In addition, a ceRNA network in CCA was constructed, composing of 50 up and 27 downregulated lncRNAs, 14 up and 7 downregulated miRNAs, 29 up and 25 downregulated mRNAs. Finally, gene set enrichment and pathway analysis indicated our CCA-specific ceRNA network was related with cancer-related pathway and molecular function. In conclusion, our research identified a novel lncRNA-related ceRNA network in CCA, which might act as a potential therapeutic target for patients with CCA.     

蜜蜂球囊菌菌丝和孢子中环状RNA的鉴定及比较分析

[目的]本研究旨在明确蜜蜂球囊菌(Ascosphaera apis,简称球囊菌)菌丝和孢子中环状RNA(circular RNA,circRNA)的数量、种类和表达谱差异,并探讨共有circRNA、特有circRNA和差异表达circRNA (differentially expressed circRNA,DEcir...     

Long noncoding RNA HOXD-AS1 induces epithelial-mesenchymal transition in breast cancer by acting as a competing endogenous RNA of miR-421

Breast cancer (BCa) is the most common malignant tumor in females. Long noncoding RNAs (lncRNAs) are deregulated in many types of human cancers, including BCa. The purpose of the present study was to examine the expression profile and biological role of HOXD cluster antisense RNA 1 (HOXD-AS1) in BCa. Our results revealed that HOXD-AS1 was upregulated in BCa tissues and cell lines, and high HOXD-AS1 expression was correlated with aggressive clinicopathological characteristics of BCa patients. Further gain-of-function and loss-of-function analysis showed that HOXD-AS1 overexpression promoted, whereas HOXD-AS1 knockdown inhibited BCa cell proliferation, cell cycle progression, migration, and invasion, indicating that HOXD-AS1 may function as a novel oncogene in BCa. Mechanistically, HOXD-AS1 could activate epithelial-mesenchymal transition (EMT) in BCa cells. We further proved that HOXD-AS1 might serve as a competing endogenous RNA of miR-421 in BCa cells, and miR-421 was downregulated and negatively correlated with HOXD-AS1 expression in BCa tissues. Besides, we confirmed that SOX4, a master regulator of EMT, was a direct target gene of miR-421. Further, rescue experiments suggested that miR-421 overexpression partly abrogated the oncogenic role of HOXD-AS1 in BCa cells. Therefore, we shed light on that HOXD-AS1/miR-421/SOX4 axis may be considered as a novel therapeutic target for the treatment of BCa patients.     

Competing endogenous RNA database

A given mRNA can be regulated by interactions with miRNAs and in turn the availability of these miRNAs can be regulated by their interactions with alternate mRNAs. The concept of regulation of a given mRNA by alternate mRNA (competing endogenous mRNA) by virtue of interactions with miRNAs through shared miRNA response elements is poised to become a fundamental genetic regulatory mechanism. The molecular basis of the mRNA-mRNA cross talks is via miRNA response elements, which can be predicted based on both molecular interaction and evolutionary conservation. By examining the co-occurrence of miRNA response elements in the mRNAs on a genome-wide basis we predict competing endogenous RNA for specific mRNAs targeted by miRNAs. Comparison of the mRNAs predicted to regulate PTEN with recently published work, indicate that the results presented within the competing endogenous RNA database (ceRDB) have biological relevance.

Availability

http://www.oncomir.umn.edu/cefinder/     

环状RNA：竞争性内源RNA新成员

环状RNA（circRNA）广泛存在于各种生物细胞中,具有结构稳定、丰度高和组织特异性表达等特征。最近的研究表明,一些circRNA作为竞争性内源NRNA（ceRNA）来发挥基因表达调控的作用。circRNA利用其microRNA（miRNA）应答元件结合miRNA,以阻断miRNA对其靶标表达的抑制作用,从而调控其他相关RNA的表达水平。circRNA在基因表达调控中重要作用的发现不仅丰富了人们对ceRNAiN控网络的认识,而且提示circRNA在药物开发和疾病诊治中具有良好的应用前景。     

环状RNA:潜在的新型miRNA活性调控分子

环状RNA(circular RNA,circRNA)是近年来RNA领域最新的研究热点.它是一类由特殊的选择性剪切产生且在真核细胞中广泛表达的环形内源性RNA分子.研究发现,circRNA富含microRNA(miRNA)结合位点,可以发挥竞争性内源RNA作用,作为miRNA"海绵"来解除对其靶基因的抑制效应.近年来,circRNA作为一种新型调控分子调控miRNA功能的发挥,受到众多研究者的青睐.本文综述circRNA的产生机制,及其调控miRNA的最新研究进展与研究方法等.