MicroRNA:新的心血管疾病生物标志物

近年来MicroRNA(miRNA)一直是医学生物学研究的热点。它作为一类非编码的小RNA,参与基因的转录和表达调控,因此人体的众多生命活动和疾病的发生、发展都与miRNA的变化密不可分。miRNA的作用因细胞特异性和目标mRNA的不同而异,miRNA可以通过影响细胞的分裂、增殖、凋亡和再生等表型的变化,参与疾病的损伤与修复过程。特别是近期研究人员进行了基于miRNA的疾病诊治研究,结果预示了良好的应用前景。     

Clinical implications of microRNAs in cancer

Abstract

MicroRNAs (miRNAs) are endogenously produced non-coding RNAs that serve as micromanagers by negatively regulating gene expression. MiRNAs are implicated in several biological pathways including development of neoplasia. Because altered miRNA expression is implicated in the pathobiology of various cancers, these molecules serve as potential therapeutic targets. Using miRNA mimics to restore levels of aberrantly down-regulated miRNAs or miRNA inhibitors to inactivate over-expressed miRNAs shows promise as the next generation of therapeutic strategies. Manipulation of miRNAs offers an alternative therapeutic approach for chemo- and radiation-resistant tumors. Similarly, miRNA expression patterns can be used for diagnosis and to predict prognosis and efficacy of therapy. We present here an overview of how miRNAs affect cancers, how they may be used as biomarkers, and the clinical implications of miRNAs in cancer.     

Protein network-based Lasso regression model for the construction of disease-miRNA functional interactions

BackgroundThere is a growing body of evidence associating microRNAs (miRNAs) with human diseases. MiRNAs are new key players in the disease paradigm demonstrating roles in several human diseases. The functional association between miRNAs and diseases remains largely unclear and far from complete. With the advent of high-throughput functional genomics techniques that infer genes and biological pathways dysregulted in diseases, it is now possible to infer functional association between diseases and biological molecules by integrating disparate biological information.ResultsHere, we first used Lasso regression model to identify miRNAs associated with disease signature as a proof of concept. Then we proposed an integrated approach that uses disease-gene associations from microarray experiments and text mining, and miRNA-gene association from computational predictions and protein networks to build functional associations network between miRNAs and diseases. The findings of the proposed model were validated against gold standard datasets using ROC analysis and results were promising (AUC=0.81). Our protein network-based approach discovered 19 new functional associations between prostate cancer and miRNAs. The new 19 associations were validated using miRNA expression data and clinical profiles and showed to act as diagnostic and prognostic prostate biomarkers. The proposed integrated approach allowed us to reconstruct functional associations between miRNAs and human diseases and uncovered functional roles of newly discovered miRNAs.ConclusionsLasso regression was used to find associations between diseases and miRNAs using their gene signature. Defining miRNA gene signature by integrating the downstream effect of miRNAs demonstrated better performance than the miRNA signature alone. Integrating biological networks and multiple data to define miRNA and disease gene signature demonstrated high performance to uncover new functional associations between miRNAs and diseases.     

常见肝炎病毒感染性疾病相关miRNA功能研究进展

病毒感染引发的疾病一直威胁着人类健康。Mi RNA是真核生物表达的一类重要的小分子RNA,可特异性的调节基因与蛋白的表达。mi RNA的研究为病毒性疾病的发生发展提供了新思路,为目前热点研究领域。随着mi RNA的研究深入,一些病毒感染中相关mi RNA的功能也被相继报道,如有些mi RNA具有抑制病毒感染宿主细胞的功能,有些mi RNA则可促进病毒在宿主细胞中的复制,有些mi RNA却参与病毒相关疾病的发生,还有些mi RNA则可作为病毒感染性疾病的特异性生物标志物。本文主要以两种常见肝炎病毒:HBV、HCV为例来系统阐述mi RNA在病毒感染中的相关功能。     

MCLPMDA: A novel method for miRNA‐disease association prediction based on matrix completion and label propagation

MiRNAs are a class of small non‐coding RNAs that are involved in the development and progression of various complex diseases. Great efforts have been made to discover potential associations between miRNAs and diseases recently. As experimental methods are in general expensive and time‐consuming, a large number of computational models have been developed to effectively predict reliable disease‐related miRNAs. However, the inherent noise and incompleteness in the existing biological datasets have inevitably limited the prediction accuracy of current computational models. To solve this issue, in this paper, we propose a novel method for miRNA‐disease association prediction based on matrix completion and label propagation. Specifically, our method first reconstructs a new miRNA/disease similarity matrix by matrix completion algorithm based on known experimentally verified miRNA‐disease associations and then utilizes the label propagation algorithm to reliably predict disease‐related miRNAs. As a result, MCLPMDA achieved comparable performance under different evaluation metrics and was capable of discovering greater number of true miRNA‐disease associations. Moreover, case study conducted on Breast Neoplasms further confirmed the prediction reliability of the proposed method. Taken together, the experimental results clearly demonstrated that MCLPMDA can serve as an effective and reliable tool for miRNA‐disease association prediction.     

Role of microRNAs in diabetes

Diabetes is one of the most common chronic diseases in the world. Multiple and complex factors including various genetic and physiological changes can lead to type 1 and type 2 diabetes. However, the major mechanisms underlying the pathogenesis of diabetes remain obscure. With the recent discovery of microRNAs (miRNAs), these small ribonucleotides have been implicated as new players in the pathogenesis of diabetes and diabetes-associated complications. MiRNAs have been shown to regulate insulin production, insulin secretion, and insulin action. This review summarizes the recent progress in the cutting-edge research of miRNAs involved in diabetes and diabetes related complications.     

昆虫miRNA研究进展

微小RNA(microRNA,miRNA)广泛存在于不同的生物体内,是一类长度为19～24 nt的内源性单链非编码小RNA,主要通过其种子区域与靶基因的开放阅读框(open reading frame,ORF)和3'非翻译区(untranslated region,UTR)进行结合,进而在转录后水平调控基因表达,miR...     

A new insight on serum microRNA expression as novel biomarkers in breast cancer patients

Breast cancer (BC) is one of the widespread lethal diseases affecting a large number of women worldwide. As such, employing and identifying significant markers for detecting BC in different stages can assist in better diagnosis and management of the disease. Several diverse markers have been introduced for diagnosis, but their limitations, including low specificity and sensitivity, reduce their application. microRNAs (miRNAs), as short noncoding RNAs, have been shown to significantly influence gene expression in different disease pathologies, especially BC. Clearly, among different samples used for detecting miRNA expressions, circulating miRNAs present as promising and useful biomarkers. Among different body fluid samples, serum serves as one of the most reliable samples, thanks to its high stability under various severe conditions and some unique features. Extensive research has suggested that BC-related miRNAs can remain stable in the serum. The objective of this review is to describe different samples used for detecting miRNAs in BC subjects with emphasis on serum miRNAs. So, this study highlights serum miRNAs with the potential of acting as biomarkers for different stages of BC. We reviewed the possible correlation between potential miRNAs and the risk of early breast cancer, metastatic breast cancer, response to chemotherapy, and relapse.     

microRNAs in kidneys: biogenesis, regulation, and pathophysiological roles

MicroRNAs (miRNA) are endogenously produced, short RNAs that repress and thus regulate the expression of almost half of known protein-coding genes. miRNA-mediated gene repression is an important regulatory mechanism to modulate fundamental cellular processes such as the cell cycle, growth, proliferation, phenotype, and death, which in turn have major influences on pathophysiological outcomes. In kidneys, miRNAs are indispensable for renal development and homeostasis. Emerging evidence has further pinpointed the pathogenic roles played by miRNAs in major renal diseases, including diabetic nephropathy, acute kidney injury, renal carcinoma, polycystic kidney disease, and others. Although the field of renal miRNA research is still in its infancy and important questions remain, future investigation on miRNA regulation in kidneys has the potential to revolutionize both the diagnosis and treatment of major renal diseases.     

Age and sex differences in kidney microRNA expression during the life span of F344 rats

Background

Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions. MiRNAs in particular have been shown to be important regulators in cancer and other diseases and show promise as predictive biomarkers for diagnosis and prognosis. In this study, we characterized the global kidney miRNA expression profile in untreated male and female F344 rats throughout the life span. These findings were correlated with sex-specific susceptibilities to adverse renal events, such as male-biased renal fibrosis and inflammation in old age.

Methods

Kidney miRNA expression was examined in F344 rats at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age in both sexes using Agilent miRNA microarrays. Differential expression was determined using filtering criteria of ≥1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively. Pathway analysis software was used to investigate the possible roles of these target genes in age- and sex-specific differences.

Results

Three hundred eleven miRNAs were found to be expressed in at least one age and sex. Filtering criteria revealed 174 differentially expressed miRNAs in the kidney; 173 and 34 miRNAs exhibiting age and sex effects, respectively. Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages. No significant sexually dimorphic miRNA expression was observed from 5 to 8 weeks, while the most differential expression (13 miRNAs) was observed at 21 weeks. Potential target genes of these differentially expressed miRNAs were identified.

Conclusions

The expression of 56% of detected renal miRNAs was found to vary significantly with age and/or sex during the life span of F344 rats. Pathway analysis suggested that 2-week-expressed miRNAs may be related to organ and cellular development and proliferation pathways. Male-biased miRNA expression at older ages correlated with male-biased renal fibrosis and mononuclear cell infiltration. These miRNAs showed high representation in renal inflammation and nephritis pathways, and included miR-214, miR-130b, miR-150, miR-223, miR-142-5p, miR-185, and miR-296*. Analysis of kidney miRNA expression throughout the rat life span will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.

Electronic supplementary material

The online version of this article (doi:10.1186/s13293-014-0019-1) contains supplementary material, which is available to authorized users.     

Detailed role of microRNA-mediated regulation of PI3K/AKT axis in human tumors

The regulation of signal transmission and biological processes, such as cell proliferation, apoptosis, metabolism, migration, and angiogenesis are greatly influenced by the PI3K/AKT signaling pathway. Highly conserved endogenous non-protein-coding RNAs known as microRNAs (miRNAs) have the ability to regulate gene expression by inhibiting mRNA translation or mRNA degradation. MiRNAs serve key role in PI3K/AKT pathway as upstream or downstream target, and aberrant activation of this pathway contributes to the development of cancers. A growing body of research shows that miRNAs can control the PI3K/AKT pathway to control the biological processes within cells. The expression of genes linked to cancers can be controlled by the miRNA/PI3K/AKT axis, which in turn controls the development of cancer. There is also a strong correlation between the expression of miRNAs linked to the PI3K/AKT pathway and numerous clinical traits. Moreover, PI3K/AKT pathway-associated miRNAs are potential biomarkers for cancer diagnosis, therapy, and prognostic evaluation. The role and clinical applications of the PI3K/AKT pathway and miRNA/PI3K/AKT axis in the emergence of cancers are reviewed in this article.     

MicroRNAs in systemic rheumatic diseases

MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNAs about 21 nucleotides in length. miRNAs have been shown to regulate gene expression and thus influence a wide range of physiological and pathological processes. Moreover, they are detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. The role of miRNAs is evident in various malignant and nonmalignant diseases, and there is accumulating evidence also for an important role of miRNAs in systemic rheumatic diseases. Abnormal expression of miRNAs has been reported in autoimmune diseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. miRNAs can be aberrantly expressed even in the different stages of disease progression, allowing miRNAs to be important biomarkers, to help understand the pathogenesis of the disease, and to monitor disease activity and effects of treatment. Different groups have demonstrated a link between miRNA expression and disease activity, as in the case of renal flares in lupus patients. Moreover, miRNAs are emerging as potential targets for new therapeutic strategies of autoimmune disorders. Taken together, recent data demonstrate that miRNAs can influence mechanisms involved in the pathogenesis, relapse, and specific organ involvement of autoimmune diseases. The ultimate goal is the identification of a miRNA target or targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the development of disease.