Screening and functional prediction of differentially expressed circRNAs in proliferative human aortic smooth muscle cells

Vascular smooth muscle cell (VSMC) proliferation is the pathological base of vascular remodelling diseases. Circular RNAs (circRNAs) are important regulators involved in various biological processes. However, the function of circRNAs in VSMC proliferation regulation remains largely unknown. This study was conducted to identify the key differentially expressed circRNAs (DEcircRNAs) and predict their functions in human aortic smooth muscle cell (HASMC) proliferation. To achieve this, DEcircRNAs between proliferative and quiescent HASMCs were detected using a microarray, followed by quantitative real‐time RT‐PCR validation. A DEcircRNA‐miRNA‐DEmRNA network was constructed, and functional annotation was performed using Gene Ontology (GO) and KEGG pathway analysis. The function of hsa_circ_0002579 in HASMC proliferation was analysed by Western blot. The functional annotation of the DEcircRNA‐miRNA‐DEmRNA network indicated that the four DEcircRNAs might play roles in the TGF‐β receptor signalling pathway, Ras signalling pathway, AMPK signalling pathway and Wnt signalling pathway. Twenty‐seven DEcircRNAs with coding potential were screened. Hsa_circ_0002579 might be a pro‐proliferation factor of HASMC. Overall, our study identified the key DEcircRNAs between proliferative and quiescent HASMCs, which might provide new important clues for exploring the functions of circRNAs in vascular remodelling diseases.     

circRNA and gastrointestinal cancer

Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs that form covalently closed continuous loops without 3′ end poly (A) tails and 5′ end caps. circRNAs are more conservative and stable than linear RNA. circRNAs can specifically bind to microRNAs as competing endogenous RNA, thereby directly or indirectly regulating the expression of related genes. circRNAs have been implicated in several cancers including gastrointestinal (GI) cancers. Some circRNAs have the potential to become biological biomarkers and therapeutic targets of GI cancers. However, the multiple functional roles of circRNAs in GI cancers remain largely unclear.     

A novel strategy of identifying circRNA biomarkers in cardiovascular disease by meta-analysis

Circular RNAs (circRNAs) are stable and abundantly expressed in vivo but are abnormally expressed in several diseases. This study aimed to identify circRNAs acting as potential biomarkers for cardiovascular disease (CVD). Research were retrieved from the articles published by September 2018 in eight databases to compare circRNA expression profiles between CVD and non-CVD in human and animal models. Meta-analysis under a random effects model was conducted. Subgroup analysis of tissue, species, and disease-specific circRNAs was examined. Sensitivity analysis was performed to explain the uncertainty among all studies. Diagnostic accuracy of circRNAs in CVD was analyzed to testify the discriminative ability. Bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was conducted. Among 6,284 differentially expressed circRNAs from 32 original studies, only 322 circRNAs were reported in three or more studies. The meta-analysis identified 63 significantly dysregulated circRNAs, 44 upregulated and 19 downregulated. Among the tissue-specific or disease-specific circRNAs identified in the subgroup analysis, two circRNAs (circCDKN2BAS and circMACF1) showed the potential to be circulating biomarkers for CVD. Sensitivity analysis demonstrated 69% of circRNAs were in conformity with the overall analysis. The pooled diagnostic odds ratio was 2.94 (95% confidence interval [CI], 2.35–3.58), and the overall area under the curve value was 0.86 (95% CI, 0.83–0.89). GO and KEGG enrichment analyses indicated that the target genes of circRNAs participate in cardiogenesis-related processes and pathways. This study demonstrates circRNAs have a high diagnostic value as potential biomarkers for CVD, and two candidate circRNAs, circCDKN2BAS and circMACF1, are potential circulating biomarkers for CVD diagnosis and treatment.     

Identification of circRNA and mRNA expression profiles and functional networks of vascular tissue in lipopolysaccharide‐induced sepsis

Sepsis is the most common cause of death in intensive care units. This study investigated the circular RNA (circRNA) and mRNA expression profiles and functional networks of the aortic tissue in sepsis. We established a lipopolysaccharide (LPS)‐induced rat sepsis model. High‐throughput sequencing was performed on the aorta tissue to identify differentially expressed (DE) circRNAs and mRNAs, which were validated by real‐time quantitative polymerase chain reaction (RT‐qPCR). Bioinformatic analysis was carried out and coding and non‐coding co‐expression (CNC) and competing endogenous RNA (ceRNA) regulatory networks were constructed to investigate the mechanisms. In total, 373 up‐regulated and 428 down‐regulated circRNAs and 2063 up‐regulated and 2903 down‐regulated mRNAs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of mRNAs showed that the down‐regulated genes were mainly enriched in the process of energy generation. CNC and ceRNA regulatory networks were constructed with seven DE circRNAs. The results of functional enrichment analysis of CNC target genes revealed the important role of circRNAs in inflammatory response. The ceRNA network also highlighted the significant enrichment in calcium signalling pathway. Significant alterations in circRNAs and mRNAs were observed in the aortic tissue of septic rats. In addition, CNC and ceRNA networks were established.     

植物环状RNA研究进展北大核心CSCD

随着高通量测序技术的发展,环状RNA (circular RNA, circRNA)逐渐成为非编码RNA研究领域的热点。CircRNA是由3′端下游供体和5′端上游受体经反向剪接形成的共价闭合环状分子,普遍存在于真核生物中。CircRNA过去被认为是错误剪接的副产物,近年来相关研究爆炸式增长,才将这种错误概念推翻。相较于动物中的大量研究,植物circRNA的研究还处于起步阶段。文中从植物circRNA的发现引入,总结了植物circRNA的环化特征、表达特异性、保守性和稳定性等特征;关注了circRNA的鉴定工具、主要类型和生成机制;归纳了植物circRNA作为microRNA(miRNA)海绵和翻译模板的潜在功能,以及在生物/非生物胁迫应答中的重要作用;简单概括了植物circRNA的降解与定位。最后讨论了植物circRNA研究存在的问题并对进一步开展植物circRNA研究进行了展望。     

环RNA研究概况

在1976年就已经发现RNA可以具有环形形式。但是长期以来对环形RNA(circRNAs)主要是作为一些特例加以研究。随着高通量RNA测序技术以及生物信息学的发展,近几年的研究发现circRNAs在真核生物中普遍存在,并且具有一定的保守性和细胞特异性。越来越多的证据指明circRNAs不是剪切噪音,而是具有一定生物学功能,可能与一系列调控甚至疾病的发生和发展相关。     

环状RNA的生物学功能及其在肿瘤发生中的作用

近年来,随着RNA研究技术的进步,研究者们在多种生物中发现了数量众多的环状RNA,且发现它们具有重要的生物学功能。环状RNA来源于内含子或外显子,可以充当微小RNA海绵,还能与蛋白质相结合,从而参与基因表达调控并影响蛋白质的功能,此外,个别环状RNA甚至能编码蛋白质。更重要的是,环状RNA在肿瘤(如:胃癌、肝癌、结直肠癌、乳腺癌、宫颈癌和卵巢癌等)的发生和发展过程中起着重要的调控作用。因此,环状RNA有希望成为肿瘤诊断的标志物和治疗的新靶点。     

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.     

MicroRNA-122a functions as a novel tumor suppressor downstream of adenomatous polyposis coli in gastrointestinal cancers

Aberrant regulation of APC/β-catenin signaling pathway is common in the pathogenesis of colorectal and other cancers. Targets regulated by APC/β-catenin signaling pathway play crucial roles in cancer development. In the current study, we aimed to illustrate the influence of APC/β-catenin signaling pathway on expression of microRNAs, one new group of players important to carcinogenesis. Restoration of APC function in colorectal cancer cells led to the deregulation of several cancer-related microRNAs, such as miR-122a which was recognized as the liver-specific microRNA. MiR-122a was down-regulated in gastrointestinal cancer cell lines as well as primary carcinoma tissues. Inhibition of miR-122a could reverse wild-type APC-induced growth inhibition of gastrointestinal cancer cells while miR-122a mimic inhibited cell growth. In summary, we identified some cancer-related microRNAs regulated by APC/β-catenin signaling pathway. The down-regulation of miR-122a mediated by aberrant APC/β-catenin signaling is important to the pathogenesis of gastrointestinal cancers.     

Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells

Tricyclodecan-9-yl-xanthogenate (D609) is a selective tumor cytotoxic agent. However, the mechanisms of action of D609 against tumor cells have not been well established. Using U937 human monocytic leukemia cells, we examined the ability of D609 to inhibit sphingomyelin synthase (SMS), since inhibition of SMS may contribute to D609-induced tumor cell cytotoxicity via modulating the cellular levels of ceramide and diacylglycerol (DAG). The results showed that D609 is capable of inducing U937 cell death by apoptosis in a dose- and time-dependent manner. The induction of U937 cell apoptosis was associated with an inhibition of SMS activity and a significant increase in the intracellular level of ceramide and decrease in that of sphingomyelin (SM) and DAG, which resulted in an elevation of the ratio between ceramide and DAG favoring the induction of apoptosis. In addition, incubation of U937 cells with C(6)-ceramide and/or H7 (a selective PKC inhibitor) reduced U937 cell viability; whereas pretreatment of the cells with a PKC activator, PMA or 1-oleoyl-2-acetylglycerol (OAG), attenuated D609-induced U937 cell apoptosis. These results suggest that SMS is a potential target of D609 and inhibition of SMS may contribute to D609-induced tumor cell death via modulation of the cellular levels of ceramide and DAG.     

Prospect of circular RNA in osteogenesis: A novel orchestrator of signaling pathways

Circular RNAs (circRNAs) were initially regarded as by-products of aberrant splicing. But now, there are substantial evidence on their various roles in the regulation of genes during the development of organs and diseases. Consistent with these breakthroughs, it is experiencing rapid growth that circRNAs function as the important checkpoints during the osteogenesis. Therefore, characterizing the roles of circRNAs is useful and critical to better understanding the process of osteogenic differentiation, which could provide new avenues for the diagnosis and treatment of bone diseases, such as bone defects and osteoporosis. In this review, we presented a map of the interaction between circRNAs and the molecules of signaling pathways associated with osteogenesis, summarized the current knowledge of the biological functions of circRNAs during the osteogenic differentiation, figured out the limits of existing research works, and provided a novel look on the diagnostic and therapeutic methods of bone diseases based on circRNAs.     

LncRNA H19: A novel oncogene in multiple cancers

Long non-coding RNAs (lncRNAs) are a series of non-coding RNAs that lack open reading frameworks. Accumulating evidence suggests important roles for lncRNAs in various diseases, including cancers. Recently, lncRNA H19 (H19) became a research focus due to its ectopic expression in human malignant tumors, where it functioned as an oncogene. Subsequently, H19 was confirmed to be involved in tumorigenesis and malignant progression in many tumors and had been implicated in promoting cell growth, invasion, migration, epithelial-mesenchymal transition, metastasis, and apoptosis. H19 also sequesters some microRNAs, facilitating a multilayer molecular regulatory mechanism. In this review, we summarize the abnormal overexpression of H19 in human cancers, which suggests wide prospects for further research into the diagnosis and treatment of cancers.     

Life without A tail: New formats of long noncoding RNAs

While most long noncoding RNAs (lncRNAs) appear indistinguishable from mRNAs, having 5′ cap structures and 3′ poly(A) tails, recent work has revealed new formats. Rather than taking advantage of the canonical cleavage and polyadenylation for their 3′ end maturation, such lncRNAs are processed and stablized by a number of other mechanisms, including the RNase P cleavage to generate a mature 3′ end, or capped by snoRNP complexes at both ends, or by forming circular structures. Importantly, such lncRNAs have also been implicated in gene expression regulation in mammalian cells. Here, we highlight recent progress in our understanding of the biogenesis and function of lncRNAs without a poly(A) tail.This paper is part of a directed issue entitled: The Non-coding RNA Revolution.     

长链非编码RNA的微RNA海绵作用与呼吸系统疾病

长链非编码RNA（long non-coding RNAs, lncRNAs）是一类由长度大于200个核苷酸组成的长链非编码序列。lncRNAs具有较长的序列,使得lncRNAs具有复杂的二级及三级结构,这也是lncRNAs结合DNA、RNA和蛋白质及其行使复杂功能的结构基础。MicroRNA（miRNAs)是长度在19到25个核苷酸之间的非编码单链RNA分子,是目前研究最多的小分子非编码RNA。而lncRNAs通过结合或者螯合miRNA来调节miRNA丰度,发挥lncRNA的“海绵”作用,从而调控一系列的病理生理过程。lncRNAs及miRNA在呼吸系统疾病的发生、发展、治疗和预后起重要作用。本文就lncRNAs及其“海绵”作用对呼吸系统疾病的影响及可能的机制进行综述。     

Pseudogene DUXAP10 can be used as a diagnostic and prognostic biomarker in human cancers

The pseudogene DUXAP10 is overexpressed in numerous types of human cancers. However, the diagnostic and prognostic value of DUXAP10 in cancers has yet to be characterized. PubMed, EMBASE, Web of Science, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus databases were comprehensively searched in this study. A total of 50 studies comprising 11,292 patients were collected in this integrated analysis. DUXAP10 was confirmed to be significantly overexpressed in various human cancers (p < .05). Summary receiver operating characteristic (SROC) curve analysis was implemented, which indicated that DUXAP10 was a potential diagnostic biomarker for human cancers (area under the curve [AUC] of SROC curve = 0.81 [0.77–0.84]; pooled sensitivity = 0.69 [0.62–0.75]; pooled specificity = 0.81 [0.73–0.87]). In addition, hazard ratios (HRs) with 95% confidence intervals (CIs) were obtained to evaluate the association of DUXAP10 expression with overall survival (OS) time of cancer patients. Outcomes of meta-analysis suggested that upregulation of DUXAP10 was closely associated with poor OS (pooled HR = 1.11 [1.03–1.18]). Our study revealed that the pseudogene DUXAP10 was upregulated in multiple types of cancers and could be a potential biomarker with good diagnostic and prognostic value for human cancers.     

A 2015 survey of established or potential epigenetic biomarkers for the accurate detection of human cancers

Context The silencing or activation of cancer-associated genes by epigenetic mechanisms can ultimately lead to the clonal expansion of cancer cells. Objective The aim of this review is to summarize all relevant epigenetic biomarkers that have been proposed to date for the diagnosis of some prevalent human cancers. Methods A Medline search for the terms epigenetic biomarkers, human cancers, DNA methylation, histone modifications and microRNAs was performed. Results One hundred fifty-seven relevant publications were found and reviewed. Conclusion To date, a significant number of potential epigenetic cancer biomarkers of human cancer have been investigated, and some have advanced to clinical implementation.