Regulation of microRNA biogenesis and turnover by animals and their viruses

MicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes.     

Role of microRNAs in malignant mesothelioma

Malignant mesothelioma (MM) is an aggressive tumor, mainly derived from the pleura, which is predominantly associated with exposure to asbestos fibers. The prognosis of MM patients is particularly severe, with a median survival of approximately 9–12 months and latency between exposure and diagnosis ranging from 20–50 years (median 30 years). Emerging evidence has demonstrated that tumor aggressiveness is associated with genome and gene expression abnormalities; therefore, several studies have recently focused on the role of microRNAs (miRNAs) in MM tumorigenesis. miRNAs are small non-protein coding single-stranded RNAs (17–22 nucleotides) involved in numerous cellular processes that negatively regulate gene expression by modulating the expression of downstream target genes. miRNAs are often deregulated in cancer; in particular, the differential miRNA expression profiles of MM cells compared to unaffected mesothelial cells have suggested potential roles of miRNAs as either oncogenes or tumor suppressor genes in MM oncogenesis. In this review, the mechanism of MM carcinogenesis was evaluated through the analysis of the published miRNA expression data. The roles of miRNAs as diagnostic biomarkers and prognostic factors for potential therapeutic strategies will be presented and discussed.     

Emerging Role of MicroRNAs in mTOR Signaling

Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase that plays a critical role in the control of cellular growth and metabolism. Hyperactivation of mTOR pathway is common in human cancers, driving uncontrolled proliferation. MicroRNA (miRNA) is a class of short noncoding RNAs that regulate the expression of a wide variety of genes. Deregulation of miRNAs is a hallmark of cancer. Recent studies have revealed interplays between miRNAs and the mTOR pathway during cancer development. Such interactions appear to provide a fine-tuning of various cellular functions and contribute qualitatively to the behavior of cancer. Here we provide an overview of current knowledge regarding the reciprocal relationship between miRNAs and mTOR pathway: regulation of mTOR signaling by miRNAs and control of miRNA biogenesis by mTOR. Further research in this area may prove important for the diagnosis and therapy of human cancer.     

Functional aspects of animal microRNAs

MicroRNAs (miRNAs) are a recently discovered family of small regulatory molecules that function by modulating protein production. There are approximately 500 known mammalian miRNA genes, and each miRNA may regulate hundreds of different protein-coding genes. Mature miRNAs bind to target mRNAs in a protein complex known as the miRNA-induced silencing complex (miRISC), sometimes referred to as the miRNP (miRNA-containing ribonucleoprotein particles), where mRNA translation is inhibited or mRNA is degraded. These actions of miRNAs have been shown to regulate several developmental and physiological processes including stem cell differentiation, haematopoiesis, cardiac and skeletal muscle development, neurogenesis, insulin secretion, cholesterol metabolism and the immune response. Furthermore, aberrant expression has been implicated in a number of diseases including cancer and heart disease. The role of miRNAs in these developmental, physiological and pathological processes will be reviewed. Received 3 August 2007; received after revision 3 October 2007; accepted 5 October 2007     

Evaluation and control of miRNA-like off-target repression for RNA interference

RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.     

MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine

MicroRNAs (miRNAs) are natural, single-stranded, small RNA molecules which subtly control gene expression. Several studies indicate that specific miRNAs can regulate heart function both in development and disease. Despite prevention programs and new therapeutic agents, cardiovascular disease remains the main cause of death in developed countries. The elevated number of heart failure episodes is mostly due to myocardial infarction (MI). An increasing number of studies have been carried out reporting changes in miRNAs gene expression and exploring their role in MI and heart failure. In this review, we furnish a critical analysis of where the frontier of knowledge has arrived in the fields of basic and translational research on miRNAs in cardiac ischemia. We first summarize the basal information on miRNA biology and regulation, especially concentrating on the feedback loops which control cardiac-enriched miRNAs. A focus on the role of miRNAs in the pathogenesis of myocardial ischemia and in the attenuation of injury is presented. Particular attention is given to cardiomyocyte death (apoptosis and necrosis), fibrosis, neovascularization, and heart failure. Then, we address the potential of miR-diagnosis (miRNAs as disease biomarkers) and miR-drugs (miRNAs as therapeutic targets) for cardiac ischemia and heart failure. Finally, we evaluate the use of miRNAs in the emerging field of regenerative medicine.     

The function of miRNA in cardiac hypertrophy

Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and non-cardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed.