Function Of Individual miRNAs Research Articles

MicroRNA profiles and functions in mosquitoes.

Mosquitoes are incriminated as vectors for many crippling diseases, including malaria, West Nile fever, Dengue fever, and other neglected tropical diseases (NTDs). microRNAs (miRNAs) can interact with multiple target genes to elicit biological functions in the mosquitoes. However, characterization and function of individual miRNAs and their potential targets have not been fully determined to date. We conducted a systematic review of published literature following PRISMA guidelines. We summarize the information about miRNAs in mosquitoes to better understand their metabolism, development, and responses to microorganisms. Depending on the study, we found that miRNAs were dysregulated in a species-, sex-, stage-, and tissue/organ-specific manner. Aberrant miRNA expressions were observed in development, metabolism, host-pathogen interactions, and insecticide resistance. Of note, many miRNAs were down-regulated upon pathogen infection. The experimental studies have expanded the identification of miRNA target from the 3′ untranslated regions (UTRs) of mRNAs of mosquitoes to the 5′ UTRs of mRNAs of the virus. In addition, we discuss current trends in mosquito miRNA research and offer suggestions for future studies.

Discovering Numerical Differences between Animal and Plant microRNAs.

Previous studies have confirmed that there are many differences between animal and plant microRNAs (miRNAs), and that numerical features based on sequence and structure can be used to predict the function of individual miRNAs. However, there is little research regarding numerical differences between animal and plant miRNAs, and whether a single numerical feature or combination of features could be used to distinguish animal and plant miRNAs or not. Therefore, in current study we aimed to discover numerical features that could be used to accomplish this. We performed a large-scale analysis of 132 miRNA numerical features, and identified 17 highly significant distinguishing features. However, none of the features independently could clearly differentiate animal and plant miRNAs. By further analysis, we found a four-feature subset that included helix number, stack number, length of pre-miRNA, and minimum free energy, and developed a logistic classifier that could distinguish animal and plant miRNAs effectively. The precision of the classifier was greater than 80%. Using this tool, we confirmed that there were universal differences between animal and plant miRNAs, and that a single feature was unable to adequately distinguish the difference. This feature set and classifier represent a valuable tool for identifying differences between animal and plant miRNAs at a molecular level.

Abstract 23: Microrna302-367 Sphingosine 1 Phosphate Receptor 1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Enhancing Vascular Stability

Angiogenic hypersprouting and leaky immature vessels of pathological angiogenesis are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs in angiogenesis and tumors has not yet been fully evaluated. Here, we show that miR302-367 elevation in endothelial cells reduces retina sprouting angiogenesis and promotes vascular stability in vivo, ex vivo and in vitro. Erk1/2 are identified as direct targets of miR302-367, and down-regulation of Erk1/2 upon miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the anti-angiogenic and vascular stabilizing effect of miR302-367 in mice. Pathological angiogenesis in tumors shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways. In conclusion, miR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth.

Abstract IA10: Notch signaling and cancer

Abstract Cancer can be seen as disease of perturbed self-renewal. In the last decades it became clear that many of the signaling pathways known to be important during embryonic development also play important roles in regulating self-renewing tissues. Deregulation of the self-renewal process results in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis all of which are hallmarks of cancer. The major question is how do these deregulated signaling cascades mechanistically contribute to cancer and are they suitable for targeting therapy? The Notch pathway is one such cascade required for normal stem cell maintenance and development of different organs. Over activation of this pathway due to mutations in the Notch receptor are found in more than 50% of human T-cell leukemia and deregulated Notch signaling has been shown to promote tumor progression of various organs. The oncogenic mediators of aberrant Notch function in T-ALL and other Notch-driven cancers appear to be manifold and complex. The modulatory function of individual miRNAs in Notch driven T-ALLs has recently been established. However, whether Dicer1-processed miRNAs are essential for Notch-driven T-ALL is currently unknown. We used conditional and inducible genetic loss of function approaches to show that development and maintenance of Notch-driven T-ALL is dependent on Dicer1 function. Lineage tracing experiments revealed that Dicer1 deficiency led to the induction of apoptosis in T-ALL cells whereas cell cycle progression remained unaltered. Through microarray-based miRNA profiling, we identified miR-21 as a previously unrecognized miRNA deregulated in both mouse and human T-ALL. Herein, we demonstrate that miR-21 regulates T-ALL cell survival via repression of the tumor suppressor Pdcd4. Moreover, we will report on the identification of a novel small molecule inhibitor (CB103) that blocks Notch signaling by interfering with the transcriptional activation complex. The compound CB103 has shown remarkable ability to block Notch signaling in human cancer cell lines as well as primary human T-ALL cells, thus abrogating their proliferative properties. In addition, compound CB103 exhibit in vivo activity as demonstrated by its ability to impinge upon Notch dependent developmental processes and by impeding tumor growth in xenograft models of human leukemia and breast cancer. Citation Format: Fabian Junker, Rajwinder Lehal, Viktoras Frimantas, Beat C. Bornhauser, Jean-Pierre Bourquin, Ute Koch, Freddy Radtke. Notch signaling and cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA10.

Aberrant microRNA expression in multiple myeloma

Multiple myeloma (MM) is a devastating disease with a complex biology, and in spite of improved survivability by novel treatment strategies over the last decade, MM is still incurable by current therapy. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at a post-transcriptional level. More than half of all protein coding genes are estimated to be controlled by miRNAs, and their expression is frequently deregulated in many diseases, including cancer. Recent studies have reported aberrant miRNA expression patterns in MM, and the function of individual miRNAs in MM has been investigated in detail in cell culture and animal models. Here, we review the current knowledge on the role of miRNAs in MM pathogenesis and discuss their potential as prognostic biomarkers and targets for treatment.

MicroRNA networks direct neuronal development and plasticity

MicroRNAs (miRNAs) constitute a class of small, non-coding RNAs that act as post-transcriptional regulators of gene expression. In neurons, the functions of individual miRNAs are just beginning to emerge, and recent studies have elucidated roles for neural miRNAs at various stages of neuronal development and maturation, including neurite outgrowth, dendritogenesis, and spine formation. Notably, miRNAs regulate mRNA translation locally in the axosomal and synaptodendritic compartments, and thereby contribute to the dynamic spatial organization of axonal and dendritic structures and their function. Given the critical role for miRNAs in regulating early brain development and in mediating synaptic plasticity later in life, it is tempting to speculate that the pathology of neurological disorders is affected by altered expression or functioning of miRNAs. Here we provide an overview of recently identified mechanisms of neuronal development and plasticity involving miRNAs, and the consequences of miRNA dysregulation.

“RISCing” the Heart

See related article, pages 18–26 MicroRNAs (miRNAs) are ≈22-nucleotide noncoding RNAs with critical functions in multiple physiological and pathological processes. Investigations into the cardiovascular functions of miRNAs were initially inspired by their disease-correlated expression signatures and their spatial/temporal-specific expression patterns during cardiovascular development.1,–,3 Severe structural and functional heart defects in mice with a cardiac-specific block in miRNA biogenesis further demonstrated the importance of miRNAs in heart.2,4 Meanwhile, loss- and gain-of-function studies by genetic or pharmacological manipulation of individual miRNAs have revealed their central roles in heart development and function.5,6 In spite of the emerging evidence linking miRNAs to heart development and disease, the biological functions and molecular mechanisms of most miRNAs remain elusive. miRNAs exert their effects primarily by base-pairing with their target mRNAs in a complex with RISC (RNA-induced silencing complex), the same ribonucleoprotein machine responsible for siRNA-mediate gene silencing. Thus, the function of individual miRNAs should be ultimately defined by the identity of its downstream mRNA targets and by the strength of these miRNA–target interactions. It has been predicted that miRNAs regulate up to 50% of all mRNAs in human genome and that, on average, each miRNA targets hundreds of mRNAs.7 Although identification of miRNA targets is a key step in dissecting miRNA mechanisms, comprehensive identification and quantitative analysis of the miRNA targets in the biologically or physiologically relevant context has been a major challenge. Bioinformatics prediction combined with experimental validation has been used as a routine approach for miRNA target determination. Numerous freely available bioinformatics tools and algorithms can be used to identify candidate miRNA targets.7 These algorithms are usually based on several criterions including: (1) sequence complementarity between miRNA seed region (the nucleotides 2 to 7 of the miRNA) and the mRNA 3′ …

Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate

Numerous microRNAs (miRNAs) have been discovered in the genomes of higher eukaryotes, and functional studies indicate that they are important during development. However, little is known concerning the function of individual miRNAs. We approached this problem in zebrafish by combining identification of miRNA expression, functional analyses and experimental validation of potential targets. We show that miR-214 is expressed during early segmentation stages in somites and that varying its expression alters the expression of genes regulated by Hedgehog signaling. Inhibition of miR-214 results in a reduction or loss of slow-muscle cell types. We show that su(fu) mRNA, encoding a negative regulator of Hedgehog signaling, is targeted by miR-214. Through regulation of su(fu), miR-214 enables precise specification of muscle cell types by sharpening cellular responses to Hedgehog.