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。     

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。     

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.     

Identification of a potential prognostic lncRNA-miRNA-mRNA signature in endometrial cancer based on the competing endogenous RNA network

Endometrial cancer is one of the most common gynecological malignant tumors. The roles of competing endogenous RNAs (ceRNAs) in this disease, however, remain unclear. In this study, we constructed a ceRNA network to reveal the core ceRNAs in endometrial cancer. Differentially expressed genes were summarized from The Cancer Genome Atlas database, whereupon 140 genes were identified for building the network. Further correlation, survival, and enrichment analyses suggested that these genes may help towards elucidating the molecular mechanisms of endometrial cancer. After validation of the findings with the GSE17025 data set, LINC00958, microRNA-761, and DOLPP1 were highlighted as the critical genes in the ceRNA network. Our work suggests that LINC00958 may regulate DOLPP1 by “sponging” miR-761 in endometrial cancer.     

ce‐Subpathway: Identification of ceRNA‐mediated subpathways via joint power of ceRNAs and pathway topologies

Competing endogenous RNAs (ceRNAs) represent a novel mechanism of gene regulation that may mediate key subpathway regions and contribute to the altered activities of pathways. However, the classical methods used to identify pathways fail to specifically consider ceRNAs within the pathways and key regions impacted by them. We proposed a powerful strategy named ce‐Subpathway for the identification of ceRNA‐mediated functional subpathways. It provided an effective level of pathway analysis via integrating ceRNAs, differentially expressed (DE) genes and their key regions within the given pathways. We respectively analysed one pulmonary arterial hypertension (PAH) and one myocardial infarction (MI) data sets and demonstrated that ce‐Subpathway could identify many subpathways whose corresponding entire pathways were ignored by those non‐ceRNA‐mediated pathway identification methods. And these pathways have been well reported to be associated with PAH/MI‐related cardiovascular diseases. Further evidence showed reliability of ceRNA interactions and robustness/reproducibility of the ce‐Subpathway strategy by several data sets of different cancers, including breast cancer, oesophageal cancer and colon cancer. Survival analysis was finally applied to illustrate the clinical application value of the ceRNA‐mediated functional subpathways using another data sets of pancreatic cancer. Comprehensive analyses have shown the power of a joint ceRNAs/DE genes and subpathway strategy based on their topologies.     

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.