miRNAs调控lincRNAs的生物信息学预测与功能分析

基因间长链非编码RNAs(Long intergenic non-coding RNAs, lincRNAs)是位于蛋白编码基因之间的长度超过200 nt的非编码RNAs, 在动物中参与细胞周期调控、免疫监视、胚胎干细胞分化等多种生物学过程, 但是lincRNAs在大多数植物中的功能尚不清楚。MicroRNAs(miRNAs)是真核生物中一类在转录水平和转录后水平介导基因沉默的21 nt左右的内源性单链小非编码RNAs分子, 通过序列互补的方式调控靶标基因的表达。目前miRNAs的靶标研究主要集中于编码蛋白的基因, 而对于靶标为非编码RNAs的研究较少, 尤其在植物中的研究更为少见。为了系统挖掘植物中lincRNAs的功能, 文章整合miRNAs数据、cDNAs数据和降解组数据, 利用生物信息学方法找到拟南芥(Arabidopsis thaliana)337个成熟miRNAs在2708个lincRNAs上的可能结合位点, 构建了miRNAs-mRNAs-lincRNAs调控网络, 并根据竞争性内源(ceRNA)假说预测lincRNAs的功能, 为进一步阐明植物中miRNAs对lincRNAs的调控机制以及lincRNAs的功能奠定了基础。     

Competitive virus and host RNAs: the interplay of a hidden virus and host interaction

During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns (PAMPs) in innate immunity. Here, considering recent research progress in microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs), we speculate that viral RNAs act as sponges and can sequester endogenous miRNAs within infected cells, thus cross-regulating the stability and translational efficiency of host mRNAs with shared miRNA response elements. This cross-talk and these reciprocal interactions between viral RNAs and host mRNAs are termed “competitive viral and host RNAs” (cvhRNAs). We further provide recent experimental evidence for the existence of cvhRNAs networks in hepatitis B virus (HBV), as well as Herpesvirus saimiri (HVS), lytic murine cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) infections. In addition, the cvhRNA hypothesis also predicts possible cross-regulation between host and other viruses, such as hepatitis C virus (HCV), HIV, influenza virus, human papillomaviruses (HPV). Since the interaction between miRNAs and viral RNAs also inevitably leads to repression of viral RNA function, we speculate that virus may evolve either to employ cvhRNA networks or to avoid miRNA targeting for optimal fitness within the host. CvhRNA networks may therefore play a fundamental role in the regulation of viral replication, infection establishment, and viral pathogenesis.     

Interaction of long noncoding RNA MEG3 with miRNAs: A reciprocal regulation

The competitive endogenous RNA (ceRNA) hypothesis suggests that a long noncoding RNA (lncRNA) can function as sinks for pools of microRNAs (miRNAs); thereby, in the presence of ceRNA, messenger RNAs (mRNAs) targeted by specific miRNAs can liberate and translate to protein. Maternally expressed gene 3 (MEG3) is a lncRNA, which its expression has been detected in various normal tissues, while it is lost or downregulated in human tumors. The MEG3 is an imprinted gene which, is methylated and suppressed by DNA methyltransferases (DNMTs) family. Also, miRNAs are involved in the regulation of MEG3 gene expression. Interestingly, the lncRNA MEG3 (lnc-MEG3), as a ceRNA affects various cell processes such as proliferation, apoptosis, and angiogenesis by sponging miRNAs. These miRNAs, in turn, regulate different mRNAs in different pathways. This review focuses on the interaction between lnc-MEG3 and experimentally validated miRNAs. In addition, the discussion supplemented by some data obtained from mirPath (v.3) and TarBase (v.8) databanks to provide more details about the pathways affected by this ceRNA.     

干细胞研究的新途径:miRNAs

微小RNA(microRNAs,miRNAs)是一类内源性的非编码单链RNA,能够通过与靶mRNA特异性的碱基配对而导致靶mRNA降解或抑制其翻译,从而对基因进行转录后调控。干细胞的自我更新和多向分化过程依赖于广泛而多样的调控机制,miRNAs正是这些调控机制中非常重要的一类分子。研究发现,干细胞的自我更新功能需要多种miRNAs的参与来维持;干细胞的分化也是多种miRNAs参与调控的结果。miRNAs可以作为干细胞研究的一个新的切入点。     

竞争性内源RNA:一种全新的基因表达调控模式

竞争性内源RNA(ceRNA)假说是一种全新的基因表达调控模式:mRNA、假基因转录物和长链非编码RNA等转录物通过microRNA应答元件竞争结合相同的microRNA来调控各自的表达水平,从而影响细胞的功能.迄今为止,多家实验室已从生物信息学、细胞生物学和动物实验等层面验证了该假说.本文追溯了ceRNA假说提出的历程,讨论了ceRNA调控网络的影响因素,并提出了一些有待进一步完善的内容.ceRNA假说大大拓展了人类基因组中功能遗传信息的范畴,也为解析一些人类疾病发生的机制提供了新线索.     

Analysis of competing endogenous RNA network identifies a poorly differentiated cancer-specific RNA signature for hepatocellular carcinoma

Plenty of evidence has suggested that long noncoding RNAs (lncRNAs) play a vital role in competing endogenous RNA (ceRNA) networks. Poorly differentiated hepatocellular carcinoma (PDHCC) is a malignant phenotype. This paper aimed to explore the effect and the underlying regulatory mechanism of lncRNAs on PDHCC as a kind of ceRNA. Additionally, prognosis prediction was assessed. A total of 943 messenger RNAs (mRNAs), 86 miRNAs, and 468 lncRNAs that were differentially expressed between 137 PDHCCs and 235 well-differentiated HCCs were identified. Thereafter, a ceRNA network related to the dysregulated lncRNAs was established according to bioinformatic analysis and included 29 lncRNAs, 9 miRNAs, and 96 mRNAs. RNA-related overall survival (OS) curves were determined using the Kaplan-Meier method. The lncRNA ARHGEF7-AS2 was markedly correlated with OS in HCC (P = .041). Moreover, Cox regression analysis revealed that patients with low ARHGEF7-AS2 expression were associated with notably shorter survival time (P = .038). In addition, the area under the curve values of the lncRNA signature for 1-, 3-, and 5-year survival were 0.806, 0.741, and 0.701, respectively. Furthermore, a lncRNA nomogram was established, and the C-index of the internal validation was 0.717. In vitro experiments were performed to demonstrate that silencing ARHGEF7-AS2 expression significantly promoted HCC cell proliferation and migration. Taken together, our findings shed more light on the ceRNA network related to lncRNAs in PDHCC, and ARHGEF7-AS2 may be used as an independent biomarker to predict the prognosis of HCC.     

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.