Research

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21 pages, 3475 KiB

Open AccessArticle

Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease—A Next-Generation Sequencing-Guided Bioinformatic Approach

by Ming-Ju Tsai, Yu-Chen Tsai, Wei-An Chang, Yi-Shiuan Lin, Pei-Hsun Tsai, Chau-Chyun Sheu, Po-Lin Kuo and Ya-Ling Hsu

Int. J. Mol. Sci. 2019, 20(3), 553; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030553 - 28 Jan 2019

Cited by 34 | Viewed by 4998

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in [...] Read more.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in bronchial epithelial cells of asthma and COPD. The microRNA profiles in primary bronchial epithelial cells from asthma (AHBE) and COPD (CHBE) patients and healthy subjects (NHBE) were analyzed with next-generation sequencing (NGS) and the significant microRNA changes common in AHBE and CHBE were extracted. The upregulation of hsa-miR-10a-5p and hsa-miR-146a-5p in both AHBE and CHBE was confirmed with quantitative polymerase chain reaction (qPCR). Using bioinformatic methods, we further identified putative targets of these microRNAs, which were downregulated in both AHBE and CHBE: miR-10a-5p might suppress BCL2, FGFR3, FOXO3, PDE4A, PDE4C, and PDE7A; miR-146a-5p might suppress BCL2, INSR, PDE4D, PDE7A, PDE7B, and PDE11A. We further validated significantly decreased expression levels of FOXO3 and PDE7A in AHBE and CHBE than in NHBE with qPCR. Increased serum miR-146a-5p level was also noted in patients with asthma and COPD as compared with normal control subjects. In summary, our study revealed possible mechanisms mediated by miR-10a-5p and miR-146a-5p in the pathogenesis of both asthma and COPD. The findings might provide a scientific basis for developing novel diagnostic and therapeutic strategies. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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Review

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18 pages, 1223 KiB

Open AccessReview

Modulators of MicroRNA Function in the Immune System

by Yunhui Jia and Yuanyuan Wei

Int. J. Mol. Sci. 2020, 21(7), 2357; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072357 - 29 Mar 2020

Cited by 43 | Viewed by 5445

Abstract

MicroRNAs (miRNAs) play a key role in fine-tuning host immune homeostasis and responses through the negative regulation of mRNA stability and translation. The pathways regulated by miRNAs are well characterized, but the precise mechanisms that control the miRNA-mediated regulation of gene expression during [...] Read more.

MicroRNAs (miRNAs) play a key role in fine-tuning host immune homeostasis and responses through the negative regulation of mRNA stability and translation. The pathways regulated by miRNAs are well characterized, but the precise mechanisms that control the miRNA-mediated regulation of gene expression during immune cell-development and immune responses to invading pathogens are incompletely understood. Context-specific interactions of miRNAs with other RNA species or proteins may modulate the function of a given miRNA. Dysregulation of miRNA function is associated with various human diseases, such as cardiovascular diseases and cancers. Here, we review the potential modulators of miRNA function in the immune system, including the transcription regulators of miRNA genes, miRNA-processing enzymes, factors affecting miRNA targeting, and intercellular communication. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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23 pages, 1118 KiB

Open AccessReview

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

by Hironori Matsuyama and Hiroshi I. Suzuki

Int. J. Mol. Sci. 2020, 21(1), 132; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010132 - 24 Dec 2019

Cited by 164 | Viewed by 12493

Abstract

MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse [...] Read more.

MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA–target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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22 pages, 11573 KiB

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Deciphering miRNAs’ Action through miRNA Editing

by Marta Correia de Sousa, Monika Gjorgjieva, Dobrochna Dolicka, Cyril Sobolewski and Michelangelo Foti

Int. J. Mol. Sci. 2019, 20(24), 6249; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246249 - 11 Dec 2019

Cited by 523 | Viewed by 24236

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called “RNA editing” involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA’s stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA’s ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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12 pages, 258 KiB

Open AccessReview

Transcription Factors Targeted by miRNAs Regulating Smooth Muscle Cell Growth and Intimal Thickening after Vascular Injury

by Levon M. Khachigian

Int. J. Mol. Sci. 2019, 20(21), 5445; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215445 - 31 Oct 2019

Cited by 14 | Viewed by 3367

Abstract

Neointima formation after percutaneous coronary intervention (PCI) is a manifestation of “phenotype switching” by vascular smooth muscle cells (SMC), a process that involves de-differentiation from a contractile quiescent phenotype to one that is richly synthetic. In response to injury, SMCs migrate, proliferate, down-regulate [...] Read more.

Neointima formation after percutaneous coronary intervention (PCI) is a manifestation of “phenotype switching” by vascular smooth muscle cells (SMC), a process that involves de-differentiation from a contractile quiescent phenotype to one that is richly synthetic. In response to injury, SMCs migrate, proliferate, down-regulate SMC-specific differentiation genes, and later, can revert to the contractile phenotype. The vascular response to injury is regulated by microRNAs (or miRNAs), small non-coding RNAs that control gene expression. Interactions between miRNAs and transcription factors impact gene regulatory networks. This article briefly reviews the roles of a range of miRNAs in molecular and cellular processes that control intimal thickening, focusing mainly on transcription factors, some of which are encoded by immediate-early genes. Examples include Egr-1, junB, KLF4, KLF5, Elk-1, Ets-1, HMGB1, Smad1, Smad3, FoxO4, SRF, Rb, Sp1 and c-Myb. Such mechanistic information could inform the development of strategies that block SMC growth, neointima formation, and potentially overcome limitations of lasting efficacy following PCI. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

17 pages, 457 KiB

Open AccessReview

Extracellular miRNAs as Biomarkers of Head and Neck Cancer Progression and Metastasis

by Zuzanna Nowicka, Konrad Stawiski, Bartłomiej Tomasik and Wojciech Fendler

Int. J. Mol. Sci. 2019, 20(19), 4799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194799 - 27 Sep 2019

Cited by 24 | Viewed by 3852

Abstract

Head and neck squamous cell carcinomas (HNSCCs) contribute to over 300,000 deaths every year worldwide. Although the survival rates have improved in some groups of patients, mostly due to new treatment options and the increasing percentage of human papillomavirus (HPV)-related cancers, local recurrences [...] Read more.

Head and neck squamous cell carcinomas (HNSCCs) contribute to over 300,000 deaths every year worldwide. Although the survival rates have improved in some groups of patients, mostly due to new treatment options and the increasing percentage of human papillomavirus (HPV)-related cancers, local recurrences and second primary tumors remain a great challenge for the clinicians. Presently, there is no biomarker for patient surveillance that could help identify patients with HNSCC that are more likely to experience a relapse or early progression, potentially requiring closer follow-up or salvage treatment. MicoRNAs (miRNAs) are non-coding RNA molecules that posttranscriptionally modulate gene expression. They are highly stable and their level can be measured in biofluids including serum, plasma, and saliva, enabling quick results and allowing for repeated analysis during and after the completion of therapy. This has cemented the role of miRNAs as biomarkers with a huge potential in oncology. Since altered miRNA expression was described in HNSCC and many miRNAs play a role in radio- and chemotherapy resistance, cancer progression, and metastasis, they can be utilized as biomarkers of these phenomena. This review outlines recent discoveries in the field of extracellular miRNA-based biomarkers of HNSCC progression and metastasis, with a special focus on HPV-related cancers and radioresistance. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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10 pages, 229 KiB

Open AccessReview

miRNA Profiling for Early Detection and Treatment of Duchenne Muscular Dystrophy

by Heather C. Hrach and Marco Mangone

Int. J. Mol. Sci. 2019, 20(18), 4638; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184638 - 19 Sep 2019

Cited by 24 | Viewed by 5293

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by out of frame mutations in the dystrophin gene. The hallmark symptoms of the condition include progressive degeneration of skeletal muscle, cardiomyopathy, and respiratory dysfunction. The most recent advances in therapeutic strategies [...] Read more.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by out of frame mutations in the dystrophin gene. The hallmark symptoms of the condition include progressive degeneration of skeletal muscle, cardiomyopathy, and respiratory dysfunction. The most recent advances in therapeutic strategies for the treatment of DMD involve exon skipping or administration of minidystrophin, but these strategies are not yet universally available, nor have they proven to be a definitive cure for all DMD patients. Early diagnosis and tracking of symptom progression of DMD usually relies on creatine kinase tests, evaluation of patient performance in various ambulatory assessments, and detection of dystrophin from muscle biopsies, which are invasive and painful for the patient. While the current research focuses primarily on restoring functional dystrophin, accurate and minimally invasive methods to detect and track both symptom progression and the success of early DMD treatments are not yet available. In recent years, several groups have identified miRNA signature changes in DMD tissue samples, and a number of promising studies consistently detected changes in circulating miRNAs in blood samples of DMD patients. These results could potentially lead to non-invasive detection methods, new molecular approaches to treating DMD symptoms, and new methods to monitor of the efficacy of the therapy. In this review, we focus on the role of circulating miRNAs in DMD and highlight their potential both as a biomarker in the early detection of disease and as a therapeutic target in the prevention and treatment of DMD symptoms. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

22 pages, 504 KiB

Open AccessReview

Exosomal MiRNAs in Pediatric Cancers

by Angela Galardi, Marta Colletti, Virginia Di Paolo, Patrizia Vitullo, Loretta Antonetti, Ida Russo and Angela Di Giannatale

Int. J. Mol. Sci. 2019, 20(18), 4600; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184600 - 17 Sep 2019

Cited by 31 | Viewed by 4524

Abstract

MicroRNAs (miRNAs) have generated great attention in oncology as they play a fundamental role in the regulation of gene expression and their aberrant expression is present in almost all types of tumors including pediatric ones. The discovery that miRNAs can be transported by [...] Read more.

MicroRNAs (miRNAs) have generated great attention in oncology as they play a fundamental role in the regulation of gene expression and their aberrant expression is present in almost all types of tumors including pediatric ones. The discovery that miRNAs can be transported by exosomes, which are vesicles of 40–120 nm involved in cellular communication, that are produced by different cell types, and that are present in different biological fluids, has opened the possibility of using exosomal miRNAs as biomarkers. The possibility to diagnose and monitor the progression and response to drugs through molecules that can be easily isolated from biological fluids represents a particularly important aspect in the pediatric context where invasive techniques are often used. In recent years, the idea of liquid biopsy as well as studies on the possible role of exosomal miRNAs as biomarkers have developed greatly. In this review, we report an overview of all the evidences acquired in recent years on the identification of exosomal microRNAs with biomarker potential in pediatric cancers. We discuss the following herein: neuroblastoma, hepatoblastoma, sarcomas (osteosarcoma, Ewing’s sarcoma and rhabdoid tumors, and non-rhabdomyosarcoma soft tissue sarcoma), brain tumors, lymphomas, and leukemias. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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26 pages, 357 KiB

Open AccessReview

Role of miRNAs in Alzheimer’s Disease and Possible Fields of Application

by Serena Silvestro, Placido Bramanti and Emanuela Mazzon

Int. J. Mol. Sci. 2019, 20(16), 3979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163979 - 15 Aug 2019

Cited by 64 | Viewed by 5125

Abstract

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3′ and 5′ untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain [...] Read more.

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3′ and 5′ untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer’s disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

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