microRNA - Articles and news items

Extracellular microRNA: the promises for the diagnostics of multiple diseases

Issue 1 2013 / 21 February 2013 / Andrey Turchinovich and Barbara Burwinkel, German Cancer Research Center

This mini-review aims to summarise recent advances in the field of molecular diagnostic of diseases using extracellular circulating miRNA in biological fluids. We will also discuss obstacles in developing miRNAs as circulating biomarkers as well as the potential future of the field.

Small non-coding RNA molecules, microRNAs, are abundantly expressed in all cell types and are involved in the regulation of key cellular processes such as metabolism, proliferation, DNA repair, apoptosis and differentiation[1-3]. There have been more than 1500 different human miRNA species discovered so far and this amount is increasing[4]. Importantly, every miRNA has a unique nucleotide sequence and miRNA expression patterns are cell type specific[5,6]. Furthermore, deregulation of certain miRNAs expression in the cell was consistently observed during certain pathologies including cancer5. Several years ago, significant amounts of miRNA were detected in all biological fluids including blood plasma, urine, tears, breast milk, amniotic fluid, cerebrospinal fluid, saliva and semen[7]. These extracellular circulating miRNAs are surprisingly stable and survive unfavourable physiological conditions such as extreme variations in pH, boiling, multiple freeze thaw cycles and extended storage. In contrast to miRNAs, common RNA species like mRNA, rRNA and tRNA are degraded within several seconds after being placed in nuclease rich extracellular environment. Together with their unique sequences and unique tissue distribution, the high stability of extracellular miRNAs makes them ideal biomarkers from a clinical diagnostic point of view. The changes in miRNA spectra observed in certain biological fluids indeed correlate with various pathological conditions, further suggesting that extracellular miRNAs can serve as informative biomarkers to assess the pathological status of the body[8,9]. (more…)

microRNA manipulation as a host-targeted antiviral therapeutic strategy

Issue 6 2011 / 13 December 2011 / Nouf N. Laqtom, University of Edinburgh & King Abdulaziz University and Amy H. Buck, University of Edinburgh

microRNAs (miRNA) are a class of non-coding RNA that regulate the precise amounts of proteins expressed in a cell at a given time. These molecules were discovered in worms in 1993 and only known to exist in humans in the last decade. Despite the youth of the miRNA field, miRNA misexpression is known to occur in a range of human disease conditions and drugs based on modulating miRNA expression are now in development for treatment of cancer, cardiovascular, metabolic and inflammatory diseases. In the last six years, an increasing number of reports have also illuminated diverse roles of cellular miRNAs in viral infection and a miRNA-targeting therapy is currently in phase II clinical trials for treatment of the Hepatitis C virus. Here we review the literature related to miRNAs that regulate viral replication and highlight the factors that will influence the use of miRNA manipulation as a broader antiviral therapeutic strategy.

microRNAs (miRNA) are a class of small noncoding RNA that bind to messenger RNAs (mRNA) and regulate the amount of specific proteins that get expressed. These small RNAs are derived from longer primary transcripts that fold back on themselves to produce stem-loop structures which are recognised and processed by Drosha and co-factors in the nucleus followed by Dicer and co-factors in the cytoplasm, resulting in a ~ 22 nucleotide (nt) duplex RNA, for review see1,2. One strand of the duplex is preferentially incorporated into the RNA-induced silencing complex (RISC) where it then mediates binding to target mRNAs. These interactions lead to decreased protein getting produced from the transcript, due to RNA destabilisation and/or inhibited translation3 (Figure 1). miRNA-mRNA recognition generally requires perfect complementarity with only the first 6-8 nt of a miRNA, termed the ‘seed’ site4. Each miRNA therefore has the potential to interact with hundreds of target mRNAs3,4 and the majority of human protein-coding genes contain miRNA binding sites under selective pressure5. Therapeutic interest in miRNAs has been supported by studies in model organisms demonstrating key functions of individual miRNAs in cancer, cardiac disease, metabolic disease, neuronal and immune cell function6. (more…)

Expression profiling of circulating miRNAs as a novel non-invasive diagnostic tool

Issue 6 2011 / 13 December 2011 / Mirco Castoldi. Department of Pediatric Hematology, Oncology and Immunology University of Heidelberg

Cell-free nucleic acids circulating in human blood were first described in 19481. However, it was not until the work of Sorengon and colleagues was published in 19942 that the importance of circulating nucleic acid (cfNA) was recognised. Today, the detection of diverse type of cfNA3 in blood and other body fluids is a valuable resource for the identification of a novel biomarker4,5. Although different types of cfNA have been described (including DNA, mRNA and microRNA), this review focuses on the isolation, detection and clinical utility of circulating microRNAs.

microRNAs (miRNAs) are an abundant class of short single stranded non-coding RNAs (~22 nts) that regulate gene expression at the posttranscriptional level. Interaction between an miRNA and any given of its mRNA targets results in either translation inhibition, mRNA degradation or a combination of both mechanisms. Therefore, miRNAs activity effectively reduces the transcriptional output of a target gene, without affecting its transcription rate. Currently, the sequence of over 60,000 microRNAs are deposited in the miRBase database [Version 17, April 20116]. miRNA activity has been associated with the control of a wide range of basic processes such as development, differentiation and metabolism. Detection of differential expression of miRNAs in many cases have established the basis for miRNA functional analysis and specific miRNA expression patterns can provide valuable diagnostic and prognostic indications, for example, in the context of human malignancies7,8. Moreover, the deregulation of the expression of miRNAs has been shown to contribute to cancer development through various kinds of mechanisms, including deletions, amplification or mutations involving miRNA loci, epigenetic silencing, as well as the dysregulation of transcription factors that target specific miRNAs9,10. (more…)

microRNAs and their potential involvement in HIV infection

Issue 3 2011 / 20 June 2011 / Guihua Sun, Irell & Manella Graduate School of Biological Science and Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope and John J. Rossi. Department of Molecular and Cellular Biology Beckman Research Institute of the City of Hope

Treatment and cure of human immunodeficiency virus-1(HIV-1) infection remains one of the greatest therapeutic challenges due to its persistent infection, often leading to acquired immunodeficiency syndrome (AIDS). Although it has been 28 years since the discovery of the virus, the development of an effective vaccine is still far away. Relatively newly discovered microRNAs (miRNA) are a family of small noncoding RNAs that can regulate gene expression primarily by binding to the 3’UTR of targeted transcripts. Understanding how HIV-1 infection affects the host miRNA pathway could shed some new insights related to the basic mechanisms underlying HIV-1 mediated pathologies and T-lymphocyte depletion. Here, we review literature related to the biogenesis of HIV-1 encoded miRNAs, cellular miRNAs that can directly target HIV-1 or essential cellular factors required for HIV-1 replication. We also discuss the feasibility of using miRNAs for HIV-1 therapy. (more…)

Sigma Life Science and SwitchGear Genomics to Co-develop Simplified Novel microRNA Target Validation System

Featured news, News / 9 August 2010 / kdm communications limited

Sigma Life Science, the innovative biological products and services research business of Sigma-Aldrich® (Nasdaq:SIAL), and SwitchGear Genomics, Inc. today announced a joint project to develop and distribute a novel microRNA (miRNA) target reporter system. Combining SwitchGear Genomics’ expertise with Sigma’s versatile lentiviral technology, these ready-to-use reporter vectors are expected to simplify miRNA target validation, enabling researchers to investigate gene regulation in a variety of biological pathways.

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Cancer-secreted microRNAs: Travelers, Messengers, and Blood-borne Biomarkers

Issue 1 2010 / 22 February 2010 /

Since the first discovery of microRNA (miRNA) from C. elegans in 19931 studies of this new class of regulatory small RNA have grown rapidly and entered a new era, where they now serve as potential biomarkers and therapeutic targets in human diseases, such as cancers. Recent studies indicating that miRNAs are aberrantly expressed in cancer, are secreted by cancer cells, and are stably present in blood open a new avenue for studying cancer at the extra/intercellular level, where miRNAs serve as important cancer-released messages.

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Small non-coding RNAs as therapeutics

Issue 2 2009, Past issues / 20 March 2009 /

For years biologists have worked to develop alternatives to traditional therapeutics. These efforts, in areas such as stem cell based and gene therapies, have received much fanfare in popular media outlets, raising expectations among the general public. This excitement may have contributed to the hasty progression of early gene therapy trials, which tragically led to several deaths. Despite early failures in the development of gene therapies, work in this field has continued, and the promise of life saving treatments remains.

Early gene therapy strategies consisted primarily of the introduction of a functional gene to compensate for a mutated or otherwise nonfunctional endogenous allele. While this approach is appropriate for many serious conditions, such as hemophilia and X-linked severe combined immunodeficiency (X-SCID), genetic diseases caused by the inappropriate upregulation of gene expression cannot be addressed by this method. An alternative approach designed to treat diseases caused by upregulated gene expression is antisense therapy, a process whereby an RNA molecule is introduced which hybridises to the mRNA of the upregulated gene in question, blocking its translation₁. (more…)

miRNA and viral infections in vertebrates

Issue 1 2009, Past issues / 7 February 2009 /

For plants and invertebrates, RNA interference is firmly established as an important antiviral mechanism. Even before Fire, Mello, and co-workers described RNA interference (RNAi) in worms in 1998₁ it was becoming clear that plants have an RNA-dependent pathway that protects against viral infections₂. The pathway, then termed post-transcriptional gene silencing (PTGS), helps plants like tobacco recover from initial viral infections and ensures that plants are protected from subsequent infections from the same or similar viral strains₃. Subsequent studies have revealed that plant PTGS and Fire and Mello’s RNAi are identical – the triggers are short RNAs derived from long double-stranded RNAs (dsRNA)₄. Incorporated into the RNA-induced silencing complex (RISC), RISC cleaves transcripts like viral messenger RNAs (mRNAs) with antisense complementary to the short RNAs.

In vertebrates, long dsRNA triggers the protein kinase R (PKR) and interferon responses which give general RNA decay and shutdown of protein synthesis. These responses are potent antiviral defences on their own and it is therefore unclear whether RNAi has the same antiviral role in vertebrates as in plants and invertebrates₅. What is becoming clear, however, is that a different aspect of the RNAi pathway is important in many vertebrate viral infections. (more…)

Detecting microRNA targets or siRNA off-targets using expression data

Issue 6 2008, Past issues / 3 December 2008 /

Recently, small RNAs such as microRNAs (miRNAs) have been demonstrated to be important regulators in both plants and animals. In animals miRNAs act as translational repressors of target genes through a combination of inhibition of translation and mRNA destabilisation. These molecules have been implicated in a multitude of diseases, including cancer and represent promising candidates for both diagnostics and therapeutics. While substantial progress has been made in the detection, sequencing and profiling of miRNAs, accurately delineating their targets remains difficult. Purely computational approaches hold much promise, yet they still suffer from over-prediction. In this article we will describe alternative approaches that utilise computational analysis combined with gene expression data to better detect miRNA effects and their targets. In particular we will describe Sylamer₁ a new tool for the detection of miRNA targets and siRNA off-target effects from expression data.

Currently there are 695 confirmed miRNAs in Human (miRBase 12)₂. One expects miRNAs to have multiple targets. However few miRNA targets have been experimentally confirmed so far. Currently, no accurate high-throughput experimental approaches exist for accurately determining miRNA target binding. Clearly, purely computational approaches are promising but while they have been shown to have high-sensitivity they can suffer from over-prediction issues₃. The key issue faced by computational approaches is that miRNAs are short (21nt) and that the key region for binding specificity is even shorter (6-8nt). Finding complementary binding sites in the 3’UTRs of potential target transcripts is hence daunting as one can find 6nt complementary sites for any miRNA across the entire genome randomly at reasonably high frequencies. (more…)

Computational prediction of microRNA and targets

Issue 5 2008, Past issues / 29 September 2008 /

MicroRNAs (miRNAs) are small (~21nucleotides), evolutionarily conserved, noncoding RNA molecules that regulate gene expression1. In mammalian genomes, conservative predictions suggest that between 500-1500 miRNAs exist. There miRNAs appear to be capable of regulating the expression of multiple genes, with many genes appearing to be regulated by multiple, different, miRNAs2. Less conservative estimates suggest their may be tens of thousands of miRNAs3 in mammalian genomes, that between 20-30% of all human genes may be subject to regulation by miRNAs, and that each miRNA may contribute to the regulation of 200 or more mRNA targets4. Therefore it is easy to see why miRNA and their potential targets have received a lot of interest in recent times, as they offer a previously unknown mechanism of fundamental molecular biology that can subtly attenuate mRNA / protein expression.

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A unique theme conference and exhibition in the MicroRNomics

Issue 5 2008, Past issues / 29 September 2008 /

On 3-4 November GeneExpression Systems, Inc., USA and the University of Cambridge, United Kingdom jointly present the Third International MicroRNA Europe 2008 Meeting on MicroRNAs: Biology to Development and Disease. 30 speakers will present the latest developments in the microRNA field. 20 poster presentations and 20 exhibit booths will also make up this uniquely themed conference and exhibition.

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Industry Insight: An interview with Søren Morgenthaler Echwald

Issue 4 2008, Past issues / 2 August 2008 /

European Pharmaceutical Review speaks to Søren Morgenthaler Echwald, Vice President of Business Development at Exiqon regarding new developments in microRNA.

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