lncRNA与miRNA相互调控作用及其与肿瘤的关系研究

长链非编码RNA (long non-coding RNA,lncRNA)是一类转录本长度大于200 bp的非编码RNA,可作为人类基因组中一类重要的调控分子通过多种方式发挥其生物学功能.近年来的研究表明,lncRNA也可以作为一种竞争性内源性RNA (competing endogenous RNA, ceRNA) 与miRNA相互作用,参与靶基因的表达调控,并在肿瘤的发生发展中发挥重要的作用.本综述在简要介绍lncRNA功能研究现状和主要研究方法的基础上,进一步分析了lncRNA与miRNA之间的互相调控关系及其在肿瘤发生发展中的作用,以便为后续的研究提供新的思路.     

非编码RNA作为ceRNA在人癌症中的功能及机制

非编码RNA(non-coding RNA, ncRNA),即无编码蛋白质潜力的RNA,包括短非编码RNA,例如微RNA(microRNA, miRNA),长非编码RNA(long coding RNA, lncRNA)和环状RNA(circular RNA, circRNA)等,已被证明可以在RNA水平上调节细胞中多种生理及病理过程。miRNA是约18～22个核苷酸大小的内源性非编码RNA分子,可以通过MRE与靶基因的3′非翻译区(untranslated region,UTR)中的互补序列结合,抑制蛋白质编码基因的表达,并导致mRNA转录物的更新、转换或降解。2011年,Salmena等提出,非编码RNA与具有编码蛋白质能力的RNA(mRNA)之间存在一种被称为竞争性内源RNA(competing endogenous RNA, ceRNA)的相互作用机制假说,即含有miRNA反应元件(MRE)的ncRNA通过与miRNA结合,解除miRNA对靶基因的抑制作用。这一假说对基因表达调控的传统认知进行了补充,在RNA水平上将多种ncRNA的作用补充到经典的miRNA调控mRNA翻译的过程,将其延伸为ceRNA-miRNA-mRNA的网络调控模式。近年来研究发现,ceRNA机制广泛存在于胃癌、结肠癌和膀胱癌等各类癌症中,并且在肿瘤的基因调控及肿瘤细胞的增殖、侵袭、转移、凋亡、细胞周期等生物过程中发挥作用。本文将介绍ceRNA及其网络的机制与分子基础,并且结合两类非编码RNA——lncRNA及circRNA作为ceRNA分别在人类不同癌症类型中的近期研究进展作一综述,讨论该机制在肿瘤中的角色及作用,以期拓宽对肿瘤发生发展机制的视野,为癌症治疗提供新思路。     

肿瘤发生过程中miRNA与lncRNA的相互作用

非编码RNA(non-coding RNA,ncRNA)是生物体内普遍存在,且对生命活动具有重要调控作用的生物分子.以微RNA（microRNA,miRNA）和长链非编码RNA（long non coding RNA,lncRNA）为代表的ncRNA分子在肿瘤发生和发展过程中都有重要的作用.越来越多研究发现,miRNA和lncRNA之间的关系是非常密切的,某些lncRNA(如H19和BIC)可以作为miRNA的前体,通过加工成miRNA而发挥作用.有些miRNA通过作用于lncRNA影响肿瘤的发生(如：miR-129与MEG3,let-7与H19);同样地,有些lncRNA通过作用于miRNA影响肿瘤的发生(如：HULC与miR-372,PTCSC3与miR-574-5p,ciRS-7与miR-7,Sry与miR-138).miRNA与lncRNA之间既可以直接相互作用,也可以通过其它分子（特别是蛋白质或蛋白质复合物）间接地影响着肿瘤的发生和发展.揭示miRNA和lncRNA相互作用在肿瘤发生中的作用可以为肿瘤的诊断和治疗提供新思路.     

lncRNA作为竞争性内源RNA在非小细胞肺癌中的作用

长链非编码RNA(long non-coding RNA,lncRNA)参与肿瘤的多种生理、病理进程.研究表明,lncRNA可通过与微小RNA (microRNA, mi RNA)反应元件相互作用,并与其他RNA分子形成竞争性内源RNA (competing endogenous RNA,ceRNA)的调控网络,参与基因的表达调控.lncRNA以ceRNA方式参与非小细胞肺癌(non-small cell lung cancer,NSCLC)的发生发展过程,为揭示NSCLC的分子机理开拓了新的思路,也为NSCLC的治疗提供新的靶点.本文在课题组前期发现NSCLC相关ceRNA基础上,主要讨论lncRNA作为ceRNA在NSCLC中高表达、低表达及治疗相关方面的作用.     

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。     

竞争内源性RNA在肿瘤中的研究进展

竞争内源性RNA (competing endogenous RNA, ceRNA)理论是解释基因表达调控和生物功能的关键线索之一。这种机制联合了不同的RNA分子,为RNA之间相互作用和RNA调控网络提供了新的见解。最近的研究证实了ceRNA调控在肿瘤发生发展中的作用,其中大多以lncRNA-miRNA-mRNA和circRNA-miRNA-mRNA调控网络为主。研究表明,多种ceRNA调控网络参与肿瘤细胞增殖、侵袭和迁移、药物抗性、血管生成以及肿瘤免疫等,影响肿瘤发展进程。该文搜集了最新的ceRNA调控肿瘤发生发展过程的研究进展,讨论在此过程中发挥关键作用的ceRNA调控网络。     

lncRNA:肿瘤分子诊断中的一颗新星

长链非编码RNA(lncRNA)是一类长度大于200个核苷酸、不具有蛋白质编码功能的转录本.许多研究已经证实,lncRNA在多种类型的肿瘤中存在异常表达,在肿瘤发生、发展中起着致癌或抑癌作用,是肿瘤发生的一类重要因素.分析lncRNA的方法有表达芯片技术、实时定量逆转录-聚合酶链反应技术、原位杂交技术和RNA深度测序技术等.目前已在组织、血液、尿液和唾液等检材中检测到肿瘤相关lncRNA.因此,lncRNA有望成为新型肿瘤标志物应用于肿瘤诊断和预后判定.     

miRNA,lncRNA与心血管疾病

近年来,心血管疾病在我国的发病率和致死率呈逐年上升趋势,已成为威胁我国公众健康的重要疾病之一.尽管长期的研究使人们对心血管疾病有了一定的了解,但是其发病机制尚未完全清楚.非编码RNA(non-coding RNA,ncRNA)是指转录组中不编码蛋白的功能性RNA分子,包括微小RNA(microRNA,miRNA)和长链非编码RNA(long non-coding RNA,lncRNA)等.miRNA是一类在进化上高度保守,具有转录后调节活性的单链非编码小分子RNA.而lncRNA是一类转录本长度超过200个核苷酸的功能性非编码RNA分子.研究表明,这些功能性ncRNA不但在细胞增殖、分化和衰老过程中发挥着重要作用,还参与了癌症、神经退行性疾病和心血管疾病等疾病的病理进程.本文将着重概述miRNA和lncRNA在心血管疾病中的作用及其最新研究进展.     

非编码RNA与妊娠期糖尿病关系的研究进展

妊娠期糖尿病(gestational diabetes mellitus, GDM)是一种常见的妊娠并发症,指在妊娠期间首次发生或诊断的自发性糖耐量异常。近年来研究发现,大量非编码RNA(non-coding RNA,ncRNA)与GDM发生、发展相关,其中包括微小RNA(microRNA, miRNA)、长链非编码RNA(long non-coding RNA, lncRNA)和环状RNA(circular RNA, circRNA)等。该综述将重点讨论miRNA、lncRNA、circRNA及其在GDM的发生、发展中的生物学作用,帮助我们更好地了解ncRNA在GDM中发挥其功能和相互作用的分子机制,为今后的研究提供信息。     

miRNA和lncRNA在动物脂肪沉积中的研究进展

微小RNA(MicroRNA,miRNA)是一类由18–25个核苷酸组成的高度保守的核苷酸序列,它可以特异性结合信使RNA (mRNA)的3′-非编码区域,进而发挥降解mRNA或阻遏mRNA翻译的负调控作用。长链非编码RNA (Long non-coding RNA,lncRNA)是一类长度超过200个核苷酸、不能编码蛋白质或只能编码蛋白质微肽的核苷酸序列,它可以在表观遗传、转录水平和转录后水平调控基因表达。脂肪作为一种重要的储能物质,在调节动物体能量平衡过程中发挥着重要的作用,并与动物产肉量、肉品质等产肉性状密切相关。而脂肪功能的紊乱可导致高血脂、Ⅱ型糖尿病以及一系列心血管疾病发生,因此动物脂肪沉积的分子调控机制备受人们关注。近年来,越来越多的研究发现miRNA和lncRNA在动物脂肪沉积中发挥重要作用。文中就现阶段miRNA和lncRNA在动物脂肪沉积中的研究进展进行综述,以期为进一步揭示动物脂肪沉积的分子调控机制提供理论指导和新思路。     

Characteristics of the competition among RNAs for the binding of shared miRNAs

Competing endogenous RNAs (ceRNAs) are RNAs that share common miRNA binding sites and compete with each other for the miRNA association at these sites. The observation of this phenomenon in the cells altered the view of the miRNA target RNAs from molecules that are passively controlled by miRNAs to molecules that also modulate the miRNAs activity. In this review, we build a general profile of ceRNAS characteristics in order to facilitate ceRNAs identification by researchers. The information summarized here contains an actualized list of previously reported ceRNAs and classes of RNAs that can participate in this type of interaction, the expression behavior and characteristics of ceRNAs and miRNAs in the context of competition, the influence of the shared MREs/miRNAs numbers and the miRNA binding strength on the competition, reports on competition between RNAs in different subcellular localizations and the concept that ceRNAs may form a huge regulatory network in the cell.     

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.     

Identification of functional lncRNAs in atrial fibrillation by integrative analysis of the lncRNA-mRNA network based on competing endogenous RNAs hypothesis

A mounting body of evidence has suggested that long noncoding RNAs (lncRNAs) play critical roles in human diseases by acting as competing endogenous RNAs (ceRNAs). However, the functions and ceRNA mechanisms of lncRNAs in atrial fibrillation (AF) remain to date unclear. In this study, we constructed an AF-related lncRNA-mRNA network (AFLMN) based on ceRNA theory, by integrating probe reannotation pipeline and microRNA (miRNA)-target regulatory interactions. Two lncRNAs with central topological properties in the AFLMN were first obtained. By using bidirectional hierarchical clustering, we identified two modules containing four lncRNAs, which were significantly enriched in many known pathways of AF. To elucidate the ceRNA interactions in certain disease or normal condition, the dysregulated lncRNA-mRNA crosstalks in AF were further analyzed, and six hub lncRNAs were obtained from the network. Furthermore, random walk analysis of the AFLMN suggested that lncRNA RP11-296O14.3 may function importantly in the pathological process of AF. All these eight lncRNAs that were identified from previous steps (RP11-363E7.4, GAS5, RP11-410L14.2, HAGLR, RP11-421L21.3, RP11-111K18.2, HOTAIRM1, and RP11-296O14.3) exhibited a strong diagnostic power for AF. The results of our study provide new insights into the functional roles and regulatory mechanisms of lncRNAs in AF, and facilitate the discovery of novel diagnostic biomarkers or therapeutic targets.     

Identification of messenger and long noncoding RNAs associated with gallbladder cancer via gene expression profile analysis

The present study aimed to investigate the long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in the progression of gallbladder cancer and explore the potential physiopathologic mechanisms of gallbladder cancer in terms of competing endogenous RNAs (ceRNAs). The original lncRNA and mRNA expression profile data (nine gallbladder cancer tissues samples and nine normal gallbladder samples) in GSE76633 was downloaded from the Gene Expression Omnibus database. Differentially expressed mRNAs and lncRNAs between gallbladder cancer tissue and normal control were selected and the pathways in which they are involved were analyzed using bioinformatics analyses. MicroRNAs (miRNAs) were also predicted based on the differentially expressed mRNAs. Finally, the co-expression relation between lncRNA and mRNA was analyzed and the ceRNA network was constructed by combining the lncRNA-miRNA, miRNA-mRNA, and lncRNA-mRNA pairs. Overall, 373 significantly differentially expressed mRNAs and 47 lncRNAs were identified between cancer and normal tissue samples. The upregulated genes were significantly enriched in the extracellular matrix (ECM)-receptor interaction pathway, while the downregulated genes were involved in the complement and coagulation cascades. Altogether, 128 co-expression relations between lncRNA and mRNA were obtained. In addition, 196 miRNA-mRNA regulatory relations and 145 miRNA-lncRNA relation pairs were predicted. Finally, the lncRNA-miRNA-gene ceRNA network was constructed by combining the three types of relation pairs, such as XLOC_011309-miR-548c-3p-SPOCK1 and XLOC_012588-miR-765-CEACAM6. mRNAs and lncRNAs may be involved in gallbladder cancer progression via ECM-receptor interaction pathways and the complement and coagulation cascades. Moreover, ceRNAs such as XLOC_011309-miR-548c-3p-SPOCK1 and XLOC_012588-miR-765-CEACAM6 can also be implicated in the pathogenesis of gallbladder cancer.     

LncRNA882 regulates leukemia inhibitory factor (LIF) by sponging miR-15b in the endometrial epithelium cells of dairy goat

Despite the fact that long noncoding RNAs (lncRNAs) play roles in almost all biological processes, little is known about their biological function in the endometrium during the formation of endometrial receptivity. In this study, a comprehensive analysis of lncRNAs in goat endometrial tissues on Day 5 (prereceptive endometrium, PE) and Day 15 (receptive endometrium, RE) of pregnancy was performed by using RNA-Seq. As a result, 668 differentially expressed lncRNAs (DELs) were found between the PE and RE. Further study showed that lncRNA882, regulated by estrogen (E2) and progestin (P4), could act as competing endogenous RNAs (ceRNAs) for miR-15b, which inhibited the expression of transforming growth factor-b-activated kinase 1 binding protein 3 (TAB3) and then indirectly regulated the level of leukemia inhibitory factor (LIF). This was helpful for the formation of endometrial receptivity in dairy goats. In conclusion, we elucidated the endometrium lncRNA profiles of PE and RE in dairy goats; lncRNA882 acted as a ceRNA for miR-15b and then indirectly regulated the level of LIF in goat endometrial epithelium cells. Thus, this study helped us to better understand the molecular regulation of endometrial receptivity in dairy goats.     

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.