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Role of MicroRNAs in Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 10046

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Dr. Lorenzo F. Sempere

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Department of Radiology & Precision Health Program, Michigan State University, Interdisciplinary Science and Technology Building, Room 218 766 Service Road, East Lansing, MI 48824, USA
Interests: tissue slide-based microRNA diagnostics; microRNA biology and evolution; cell type-specific activities of microRNAs in oncology with a focus on breast and pancreatic cancer; nanoparticle-based delivery of microRNA activity modulators
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Dear Colleagues,

MicroRNAs are an abundant class of short non-coding RNAs. MicroRNAs regulate gene expression predominantly at the posttranscriptional stage by interacting with partially complementary binding sites on the 3′ UTR of mRNAs of their target genes. Through this mode of regulation and via coordinated interactions with multiple target genes, many miRNAs have been etiologically and mechanistically linked to a variety of human diseases. More than 1900 entries of short non-coding RNA sequences have been registered with miRBase.org for the human genome. Furthermore, 546 of these entries have been curated as bona fide microRNA genes as per mirgenedb.org.

The human miRNome has distinct evolutionary origins; some human microRNAs are conserved in all animals (bilateria), whereas other human microRNAs have more recent origins being specific to eutheria (placental animals), primates, or even restricted to only humans. The evolutionary origin of some miRNAs provides clues of their role in human development, physiology, and pathological processes. Similarly, the tissue- and cell type-specific expression (e.g., muscle cells, neurons, hepatocytes) of some miRNAs offers clues of their biological activity and regulatory networks.

This Special Issue will provide a comprehensive update on the latest findings of human disease–associated miRNAs, with a focus on the clinical application of miRNAs as biomarkers for diagnosis and prognosis, treatment prediction, and miRNA-based therapeutic strategies. Given the broad implication of microRNAs in human diseases, we expect this Special Issue to cover different human diseases from cancer to cardiovascular disease to neurological conditions and degenerative diseases.

We welcome both original research papers and review articles that describe advances in deciphering the etiological and epidemiological links of microRNAs to human diseases, detection methodology and bioinformatics approaches to uncover miRNA signatures, fundamental biology and molecular approaches to determine the mechanistic details of miRNA contribution to human diseases, and diagnostic and therapeutic development to apply this knowledge for the treatment of human diseases in first-in-human clinical trials.

Dr. Lorenzo F. Sempere
Guest Editor

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Keywords

microRNAs, miRNAs, miRs
preclinical models
target interaction, regulatory networks
oncology, cancer biology
cardiovascular disease
neurodegenerative conditions
diagnostic applications
therapeutic development and clinical trials

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Published Papers (7 papers)

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Research

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17 pages, 7511 KiB

Open AccessArticle

Mesenchymal Stem Cell-Exosomal miR-99a Attenuate Silica-Induced Lung Fibrosis by Inhibiting Pulmonary Fibroblast Transdifferentiation

by Xiaohui Hao, Peiyuan Li, Yudi Wang, Qinxin Zhang and Fang Yang

Int. J. Mol. Sci. 2024, 25(23), 12626; https://doi.org/10.3390/ijms252312626 - 25 Nov 2024

Viewed by 573

Abstract

Silicosis is one of the most prevalent and fatal occupational diseases worldwide, with unsatisfactory clinical outcomes. This study aimed to investigate the therapeutic effect and related molecular mechanisms of how mesenchymal stem cell (MSC)-secreted exosomes alleviate SiO₂-induced pulmonary fibrosis. miR-99a-5p was significantly downregulated in silicosis models via high-throughput miRNA screening, and was overlapped with miRNAs in exosomes from MSCs. miR-99a-5p was significantly downregulated in the lung of a mice silicosis model and in TGFβ1-induced NIH-3T3 cells. In contrast, fibroblast growth factor receptor 3 (FGFR3), a direct target gene of miR-99a-5p, was upregulated in vitro and in vivo. Furthermore, we demonstrated that MSC-derived exosomes deliver enriched miR-99a-5p to target cells and inhibit TGF-β1-induced fibroblast transdifferentiation to reduce collagen protein production. Similarly, in a silicosis mouse model, MSC-derived exosome treatment through the tail veins of the mice counteracted the upregulation of fibrosis-related proteins and collagen deposition in the lung of the mice. By constructing exosomal therapeutic cell models with different miR-99a expressions, we further demonstrated that miR-99a-5p might attenuate pulmonary fibrosis by regulating target protein FGFR3 and downstream mitogen-activated protein kinase (MAPK) signalling pathways. Our study demonstrated that MSC-derived exosomes ameliorate SiO₂-induced pulmonary fibrosis by inhibiting fibroblast transdifferentiation and represent an attractive method of pulmonary fibrosis treatment. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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11 pages, 423 KiB

Open AccessArticle

Association of MicroRNA Expression and Serum Neurofilament Light Chain Levels with Clinical and Radiological Findings in Multiple Sclerosis

by María Inmaculada Domínguez-Mozo, Ignacio Casanova, Enric Monreal, Lucienne Costa-Frossard, Susana Sainz-de-la-Maza, Raquel Sainz-Amo, Yolanda Aladro-Benito, Pedro Lopez-Ruiz, Laura De-Torres, Sara Abellán, Maria Angel Garcia-Martinez, David De-la-Cuesta, Daniel Lourido, Angel Torrado-Carvajal, Carol Gomez-Barbosa, Carla Linares-Villavicencio, Luisa Maria Villar, Carlos López-De-Silanes, Rafael Arroyo and Roberto Alvarez-Lafuente

Int. J. Mol. Sci. 2024, 25(18), 10012; https://doi.org/10.3390/ijms251810012 - 17 Sep 2024

Viewed by 1135

Abstract

microRNAs (miRNAs) are promising biomarkers for many diseases, including multiple sclerosis (MS). The neurofilament light chain (NfL) is a biomarker that can detect axonal damage in different neurological diseases. The objective of this study was to evaluate the association of the expression profile of pre-selected miRNAs and NfL levels with clinical and radiological variables in MS patients. We conducted a 1-year longitudinal prospective study in MS patients with different clinical forms. We measured clinical disability using the expanded disability status scale (EDSS), the magnetic resonance imaging (MRI) volumetry baseline, and cognitive functioning using the processing speed test (PST) at baseline and 1 year later. Selected serum miRNAs and serum NfL (sNfL) levels were quantified. Seventy-three patients were recruited. MiR-126.3p correlated with EDSS and cognitive status at baseline and miR-126.3p and miR-9p correlated with cognitive deterioration at 1 year. Correlations with regional brain volumes were observed between miR-126.3p and the cortical gray matter, cerebellum, putamen, and pallidum; miR-146a.5p with the cerebellum and pallidum; miR-29b.3p with white matter and the pallidum; miR-138.5p with the pallidum; and miR-9.5p with the thalamus. sNfL was correlated with miR-9.5p. miR-146a.5p was also associated with the MS phenotype. These data justify future studies to further explore the utility of miRNAs (mirR-126.3p, miR-146.5p, and miR.9-5p) and sNfL levels as biomarkers of MS. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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21 pages, 26487 KiB

Open AccessArticle

Master Regulators of Causal Networks in Intestinal- and Diffuse-Type Gastric Cancer and the Relation to the RNA Virus Infection Pathway

by Shihori Tanabe, Sabina Quader, Horacio Cabral, Edward J. Perkins, Hiroshi Yokozaki and Hiroki Sasaki

Int. J. Mol. Sci. 2024, 25(16), 8821; https://doi.org/10.3390/ijms25168821 - 13 Aug 2024

Viewed by 1173

Abstract

Causal networks are important for understanding disease signaling alterations. To reveal the network pathways affected in the epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to the poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) were analyzed. The network pathways in GC were analyzed using Ingenuity Pathway Analysis (IPA). The analysis of the probe sets in which the gene expression had significant differences between diffuse- and intestinal-type GC in RNA sequencing of the publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of EMT regulation via the growth factors pathway, the coronavirus pathogenesis pathway, and vorinostat. The network had RNA–RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-223, mir-25, mir-27, mir-29, and mir-34. The molecular networks revealed in the study may lead to identifying drug targets for GC. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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12 pages, 2114 KiB

Open AccessArticle

Regulation of TIR-1/SARM-1 by miR-71 Protects Dopaminergic Neurons in a C. elegans Model of LRRK2-Induced Parkinson’s Disease

by Devin Naidoo and Alexandre de Lencastre

Int. J. Mol. Sci. 2024, 25(16), 8795; https://doi.org/10.3390/ijms25168795 - 13 Aug 2024

Cited by 1 | Viewed by 1100

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by symptoms such as bradykinesia, resting tremor, and rigidity, primarily driven by the degradation of dopaminergic (DA) neurons in the substantia nigra. A significant contributor to familial autosomal dominant PD cases is mutations in the LRRK2 gene, making it a primary therapeutic target. This study explores the role of microRNAs (miRNAs) in regulating the proteomic stress responses associated with neurodegeneration in PD using C. elegans models. Our focus is on miR-71, a miRNA known to affect stress resistance and act as a pro-longevity factor in C. elegans. We investigated miR-71’s function in C. elegans models of PD, where mutant LRRK2 expression correlates with dopaminergic neuronal death. Our findings reveal that miR-71 overexpression rescues motility defects and slows dopaminergic neurodegeneration in these models, suggesting its critical role in mitigating the proteotoxic effects of mutant LRRK2. Conversely, miR-71 knockout exacerbates neuronal death caused by mutant LRRK2. Additionally, our data indicate that miR-71’s neuroprotective effect involves downregulating the toll receptor domain protein tir-1, implicating miR-71 repression of tir-1 as vital in the response to LRRK2-induced proteotoxicity. These insights into miR-71’s role in C. elegans models of PD not only enhance our understanding of molecular mechanisms in neurodegeneration but also pave the way for potential research into human neurodegenerative diseases, leveraging the conservation of miRNAs and their targets across species. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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14 pages, 2493 KiB

Open AccessArticle

Acute Effects of Dietary Protein Consumption on the Postprandial Metabolic Response, Amino Acid Levels and Circulating MicroRNAs in Patients with Obesity and Insulin Resistance

by Karla G. Hernández-Gómez, Laura A. Velázquez-Villegas, Omar Granados-Portillo, Azalia Avila-Nava, Luis E. González-Salazar, Aurora E. Serralde-Zúñiga, Berenice Palacios-González, Edgar Pichardo-Ontiveros, Rocio Guizar-Heredia, Adriana M. López-Barradas, Mónica Sánchez-Tapia, Violeta Larios-Serrato, Viridiana Olin-Sandoval, Andrea Díaz-Villaseñor, Isabel Medina-Vera, Lilia G. Noriega, Gabriela Alemán-Escondrillas, Victor M. Ortiz-Ortega, Nimbe Torres, Armando R. Tovar and Martha Guevara-Cruz Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(14), 7716; https://doi.org/10.3390/ijms25147716 - 14 Jul 2024

Cited by 1 | Viewed by 1408

Abstract

The post-nutritional intervention modulation of miRNA expression has been previously investigated; however, post-acute dietary-ingestion-related miRNA expression dynamics in individuals with obesity and insulin resistance (IR) are unknown. We aimed to determine the acute effects of protein ingestion from different dietary sources on the postprandial metabolic response, amino acid levels, and circulating miRNA expression in adults with obesity and IR. This clinical trial included adults with obesity and IR who consumed (1) animal-source protein (AP; calcium caseinate) or (2) vegetable-source protein (VP; soy protein isolate). Glycaemic, insulinaemic, and glucagon responses, amino acid levels, and exosomal microRNAs isolated from plasma were analysed. Post-AP ingestion, the area under the curve (AUC) of insulin (p = 0.04) and the plasma concentrations of branched-chain (p = 0.007) and gluconeogenic (p = 0.01) amino acids increased. The effects of different types of proteins on the concentration of miRNAs were evaluated by measuring their plasma circulating levels. Compared with the baseline, the AP group presented increased circulating levels of miR-27a-3p, miR-29b-3p, and miR-122-5p (p < 0.05). Subsequent analysis over time at 0, 30, and 60 min revealed the same pattern and differences between treatments. We demonstrated that a single dose of dietary protein has acute effects on hormonal and metabolic regulation and increases exosomal miRNA expression in individuals with obesity and IR. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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24 pages, 6271 KiB

Open AccessArticle

miRNA Expression Profiles in Isolated Ventricular Cardiomyocytes: Insights into Doxorubicin-Induced Cardiotoxicity

by Yohana Domínguez Romero, Gladis Montoya Ortiz, Susana Novoa Herrán, Jhon Osorio Mendez and Luis A. Gomez Grosso

Int. J. Mol. Sci. 2024, 25(10), 5272; https://doi.org/10.3390/ijms25105272 - 12 May 2024

Cited by 1 | Viewed by 1964

Abstract

Doxorubicin (DOX), widely used as a chemotherapeutic agent for various cancers, is limited in its clinical utility by its cardiotoxic effects. Despite its widespread use, the precise mechanisms underlying DOX-induced cardiotoxicity at the cellular and molecular levels remain unclear, hindering the development of preventive and early detection strategies. To characterize the cytotoxic effects of DOX on isolated ventricular cardiomyocytes, focusing on the expression of specific microRNAs (miRNAs) and their molecular targets associated with endogenous cardioprotective mechanisms such as the ATP-sensitive potassium channel (KATP), Sirtuin 1 (SIRT1), FOXO1, and GSK3β. We isolated Guinea pig ventricular cardiomyocytes by retrograde perfusion and enzymatic dissociation. We assessed cell morphology, Reactive Oxygen Species (ROS) levels, intracellular calcium, and mitochondrial membrane potential using light microscopy and specific probes. We determined the miRNA expression profile using small RNAseq and validated it using stem-loop qRT-PCR. We quantified mRNA levels of some predicted and validated molecular targets using qRT-PCR and analyzed protein expression using Western blot. Exposure to 10 µM DOX resulted in cardiomyocyte shortening, increased ROS and intracellular calcium levels, mitochondrial membrane potential depolarization, and changes in specific miRNA expression. Additionally, we observed the differential expression of KATP subunits (ABCC9, KCNJ8, and KCNJ11), FOXO1, SIRT1, and GSK3β molecules associated with endogenous cardioprotective mechanisms. Supported by miRNA gene regulatory networks and functional enrichment analysis, these findings suggest that DOX-induced cardiotoxicity disrupts biological processes associated with cardioprotective mechanisms. Further research must clarify their specific molecular changes in DOX-induced cardiac dysfunction and investigate their diagnostic biomarkers and therapeutic potential. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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30 pages, 2358 KiB

Open AccessReview

Insights into the Role of microRNAs as Clinical Tools for Diagnosis, Prognosis, and as Therapeutic Targets in Alzheimer’s Disease

by Nidhi Puranik and Minseok Song

Int. J. Mol. Sci. 2024, 25(18), 9936; https://doi.org/10.3390/ijms25189936 - 14 Sep 2024

Viewed by 1643

Abstract

Neurodegenerative diseases (NDDs) are a diverse group of neurological disorders characterized by alterations in the structure and function of the central nervous system. Alzheimer’s disease (AD), characterized by impaired memory and cognitive abilities, is the most prevalent type of senile dementia. Loss of synapses, intracellular aggregation of hyperphosphorylated tau protein, and extracellular amyloid-β peptide (Aβ) plaques are the hallmarks of AD. MicroRNAs (miRNAs/miRs) are single-stranded ribonucleic acid (RNA) molecules that bind to the 3′ and 5′ untranslated regions of target genes to cause post-transcriptional gene silencing. The brain expresses over 70% of all experimentally detected miRNAs, and these miRNAs are crucial for synaptic function and particular signals during memory formation. Increasing evidence suggests that miRNAs play a role in AD pathogenesis and we provide an overview of the role of miRNAs in synapse formation, Aβ synthesis, tau protein accumulation, and brain-derived neurotrophic factor-associated AD pathogenesis. We further summarize and discuss the role of miRNAs as potential therapeutic targets and biomarkers for AD detection and differentiation between early- and late-stage AD, based on recent research. In conclusion, altered expression of miRNAs in the brain and peripheral circulation demonstrates their potential as biomarkers and therapeutic targets in AD. Full article

(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases)

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