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Advances in Clinical and Experimental... Dec 2020MicroRNAs (miRs) are small non-coding RNAs. MiR-125b has been described as being downregulated in cataract tissue when compared to a transparent lens.
BACKGROUND
MicroRNAs (miRs) are small non-coding RNAs. MiR-125b has been described as being downregulated in cataract tissue when compared to a transparent lens.
OBJECTIVES
The aims of the study were: 1) to establish the expression of miR-125b in cataracts complicated by pseudoexfoliation syndrome (PEX), glaucoma or PEX glaucoma; and 2) to determine whether any environmental factors influence miR-125b expression.
MATERIAL AND METHODS
Anterior lens capsules were obtained from 150 patients. The patients were subdivided into 1 of 4 groups: those with PEX (PEXg), those with primary open-angle glaucoma (Gg) and those with PEX glaucoma (PEXGg), plus gender-matched controls with cataracts alone (control group - Cg). Quantitative polymerase chain reaction (qPCR) expression of microRNA-125b was examined in every group.
RESULTS
The mean age of the 150 patients was 75.18 years (standard deviation (SD) ±9.12 years). Our investigation indicated, for the first time, that miR-125b expression was increased 3.33 times in the PEXg (p = 0.015). The quantitative analysis of miR-125b expression conducted between combined groups of all the patients that have PEX syndrome (with or without glaucoma) and the Cg revealed a statistically significant difference (p = 0.04). Lower miR-125b expression was found in the patients who smoked compared to those who did not (p = 0.01).
CONCLUSIONS
Our data revealed the possible role of miR-125b in PEX syndrome development. There are 2 possible interpretations of these results: either the co-existence of PEX acts as a moderator of miR-125b expression in the anterior lens capsule, or increased expression of miR-125b can play a role in the pathogenesis of PEX.
Topics: Aged; Cataract; Exfoliation Syndrome; Gene Expression Regulation; Glaucoma; Humans; MicroRNAs
PubMed: 33389830
DOI: 10.17219/acem/123623 -
Journal of Hematology & Oncology Jun 2023We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated...
Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study.
BACKGROUND
We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation.
METHODS
In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0-2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33).
RESULTS
Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3-4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose.
CONCLUSIONS
The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).
Topics: Humans; MicroRNAs; Neoplasms; Oligonucleotides
PubMed: 37365583
DOI: 10.1186/s13045-023-01468-8 -
Current Medical Science Jun 2022Glioblastoma (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and high recurrence rate. It's known that some microRNAs...
OBJECTIVE
Glioblastoma (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and high recurrence rate. It's known that some microRNAs (miRNAs) which are associated with tumorigenesis and progression can be considered as prognostic and therapeutic targets in tumors including GBM. This study aims to highlight the potential role of the core miRNAs in GBM and their potential use as a prognostic and therapeutic biomarker.
METHODS
Differentially expressed miRNAs (DEmiRNAs) were identified in GBM by integrating miRNA-sequencing results and a GBM microarray dataset from the Gene Expression Omnibus (GEO) database through bioinformatics tools. The dysregulated miRNAs were identified by survival analysis through Chinese Glioma Genome Atlas (CGGA). Target genes of the dysregulated miRNAs were predicted on MiRWalk and miRTarBase database. TAM2.0 database, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were used to analyze the function of the dysregulated miRNAs. Subsequently, protein-protein interaction (PPI) network analysis was used to identify the top 20 hub targets of the up-regulated and down-regulated miRNAs, respectively. Then, core miRNAs in GBM were identified by constructing dysregulated miRNA-differentially expressed hub gene networks. Validation of the core miRNAs expression was detected in 41 GBM tissues compared to 8 normal brain tissues. Furthermore, the potential biomarkers were identified by clinical correlation analysis and survival analysis.
RESULTS
Totally, 68 intersecting DEmiRNAs were identified, 40 of which were upregulated and the other 28 miRNAs were downregulated. Two upregulated and 4 downregulated miRNAs showed prognostic significance. Most differentially expressed hub genes were regulated by the miR-28-5p and miR-1224-5p, which were respectively upregulated and downregulated in GBM. The correlation between miR-1224-5p level and recurrence was statistically significant (P=0.011). Survival analysis showed that high miR-28-5p level and high miR-1224-5p level were both associated with better prognosis. Moreover, high miR-1224-5p level was an independent prognosis factor for GBM patients according to the cox regression analysis.
CONCLUSION
MiRNA-1224-5p could be a potential target for the prognosis and treatment in GBM.
Topics: Biomarkers; Computational Biology; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; MicroRNAs; Prognosis
PubMed: 35678909
DOI: 10.1007/s11596-022-2593-5 -
Translational Research : the Journal of... Apr 2021A fraction of the transcriptome is translated into proteins. The rest is classified as non-protein coding RNA (Ribonucleic Acid) but has gained increased attention as... (Review)
Review
A fraction of the transcriptome is translated into proteins. The rest is classified as non-protein coding RNA (Ribonucleic Acid) but has gained increased attention as functional and regulatory group of transcripts. The gene regulatory role of non-coding RNAs (ncRNAs) has now been widely accepted in diverse biological processes in both physiology and disease. MicroRNAs fall into this latter group and are widely known for their diverse post-transcriptional regulatory role. MicroRNA sequences are embedded in the long ncRNAs, known as primary microRNAs, are processed into precursor microRNAs and are typically transported out of the nucleus for maturation and loading into a protein complex forming RNA-induced silencing complex (RISC) that either drives the degradation of messenger RNA (mRNA) or blocks its translation. A new phenomenon is emerging where microRNAs have active roles within the nucleus. The presence of RISC components including microRNAs in the nucleus supports this notion. They may integrate with chromatin modifiers, microprocessing machinery and mRNA stabilizing transcripts to play a multifunctional role in the nucleus. Although a limited number of studies appreciate this novel activity of microRNAs relevant to the cardiovascular system, they provide proof-of-concept that requires consideration while targeting miRNAs with therapeutic potential.
Topics: Animals; Cardiovascular Physiological Phenomena; Cardiovascular System; Cell Nucleus; Gene Expression Regulation; Humans; MicroRNAs
PubMed: 33186782
DOI: 10.1016/j.trsl.2020.11.004 -
Genes & Development May 2023DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have...
DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140) lacking the PRD, which is produced by proteolytic cleavage. Small RNA sequencing revealed that p140 is significantly impaired in the maturation of intronic miRNAs. Consistently, our minigene constructs demonstrated that PRD enhances the processing of intronic hairpins, but not those in exons. Splice site mutations did not affect the PRD's enhancing effect on intronic constructs, suggesting that the PRD acts independently of splicing reaction by interacting with sequences residing within introns. The N-terminal regions from zebrafish and DROSHA can replace the human counterpart, indicating functional conservation despite poor sequence alignment. Moreover, we found that rapidly evolving intronic miRNAs are generally more dependent on PRD than conserved ones, suggesting a role of PRD in miRNA evolution. Our study reveals a new layer of miRNA regulation mediated by a low-complexity disordered domain that senses the genomic contexts of miRNA loci.
Topics: Animals; Humans; Introns; MicroRNAs; Proline; Ribonuclease III; RNA Processing, Post-Transcriptional; Zebrafish
PubMed: 37236670
DOI: 10.1101/gad.350275.122 -
Molecular Neurodegeneration Nov 2021MicroRNA (miRNA) expression in the brain is altered in neurodegenerative diseases. Recent studies demonstrated that selected miRNAs conventionally regulating gene...
BACKGROUND
MicroRNA (miRNA) expression in the brain is altered in neurodegenerative diseases. Recent studies demonstrated that selected miRNAs conventionally regulating gene expression at the post-transcriptional level can act extracellularly as signaling molecules. The identity of miRNA species serving as membrane receptor ligands involved in neuronal apoptosis in the central nervous system (CNS), as well as the miRNAs' sequence and structure required for this mode of action remained largely unresolved.
METHODS
Using a microarray-based screening approach we analyzed apoptotic cortical neurons of C56BL/6 mice and their supernatant with respect to alterations in miRNA expression/presence. HEK-Blue Toll-like receptor (TLR) 7/8 reporter cells, primary microglia and macrophages derived from human and mouse were employed to test the potential of the identified miRNAs released from apoptotic neurons to serve as signaling molecules for the RNA-sensing receptors. Biophysical and bioinformatical approaches, as well as immunoassays and sequential microscopy were used to analyze the interaction between candidate miRNA and TLR. Immunocytochemical and -histochemical analyses of murine CNS cultures and adult mice intrathecally injected with miRNAs, respectively, were performed to evaluate the impact of miRNA-induced TLR activation on neuronal survival and microglial activation.
RESULTS
We identified a specific pattern of miRNAs released from apoptotic cortical neurons that activate TLR7 and/or TLR8, depending on sequence and species. Exposure of microglia and macrophages to certain miRNA classes released from apoptotic neurons resulted in the sequence-specific production of distinct cytokines/chemokines and increased phagocytic activity. Out of those miRNAs miR-100-5p and miR-298-5p, which have consistently been linked to neurodegenerative diseases, entered microglia, located to their endosomes, and directly bound to human TLR8. The miRNA-TLR interaction required novel sequence features, but no specific structure formation of mature miRNA. As a consequence of miR-100-5p- and miR-298-5p-induced TLR activation, cortical neurons underwent cell-autonomous apoptosis. Presence of miR-100-5p and miR-298-5p in cerebrospinal fluid led to neurodegeneration and microglial accumulation in the murine cerebral cortex through TLR7 signaling.
CONCLUSION
Our data demonstrate that specific miRNAs are released from apoptotic cortical neurons, serve as endogenous TLR7/8 ligands, and thereby trigger further neuronal apoptosis in the CNS. Our findings underline the recently discovered role of miRNAs as extracellular signaling molecules, particularly in the context of neurodegeneration.
Topics: Animals; Cerebral Cortex; Ligands; Mice; MicroRNAs; Neurons; Toll-Like Receptor 7
PubMed: 34838071
DOI: 10.1186/s13024-021-00498-5 -
Biomolecules May 2023In this study, we conducted a systematic review and meta-analysis to summarize and evaluate the global research potential of different circulating miRNAs as an early... (Meta-Analysis)
Meta-Analysis Review
In this study, we conducted a systematic review and meta-analysis to summarize and evaluate the global research potential of different circulating miRNAs as an early diagnostic biomarker for OC. A systematic literature search for relevant studies was conducted in June 2020 and followed up in November 2021. The search was conducted in English databases (PubMed, ScienceDirect). The primary search resulted in a total of 1887 articles, which were screened according to the prior established inclusion and exclusion criteria. We identified 44 relevant studies, of which 22 were eligible for the quantitative meta-analysis. Statistical analysis was performed using the Meta-package in Rstudio. Standardized mean differences (SMD) of relative levels between control subjects and OC patients were used to evaluate the differential expression. All studies were quality evaluated using a Newcastle-Ottawa Scale. Based on the meta-analysis, nine miRNAs were identified as dysregulated in OC patients compared to controls. Nine were upregulated in OC patients compared to controls (miR-21, -125, -141, -145, -205, -328, -200a, -200b, -200c). Furthermore, miR-26, -93, -106 and -200a were analyzed, but did not present an overall significant difference between OC patients and controls. These observations should be considered when performing future studies of circulating miRNAs in relation to OC: sufficient size of clinical cohorts, development of consensus guidelines for circulating miRNA measurements, and coverage of previously reported miRNAs.
Topics: Humans; Female; Circulating MicroRNA; Biomarkers, Tumor; Ovarian Neoplasms; MicroRNAs; Early Diagnosis
PubMed: 37238740
DOI: 10.3390/biom13050871 -
Pediatric Critical Care Medicine : a... Apr 2020We investigated whether concentrations of circulating microRNAs differ across the hypertensive right ventricle and pulmonary circulation, and correlate with...
OBJECTIVES
We investigated whether concentrations of circulating microRNAs differ across the hypertensive right ventricle and pulmonary circulation, and correlate with hemodynamic/echocardiographic variables in patients with pulmonary arterial hypertension versus nonpulmonary arterial hypertension controls.
DESIGN
Prospective blood collection during cardiac catheterization from the superior vena cava, pulmonary artery, and ascending aorta in 12 children with pulmonary arterial hypertension and nine matched nonpulmonary arterial hypertension controls, followed by an unbiased quantitative polymerase chain reaction array screen for 754 microRNAs in plasma.
SETTING
Children's hospital at a medical school.
PATIENTS
Twelve pulmonary arterial hypertension patients included as follows: idiopathic pulmonary arterial hypertension (5), pulmonary arterial hypertension (2), pulmonary arterial hypertension-repaired congenital heart disease (4), portopulmonary pulmonary hypertension (1). Nine nonpulmonary arterial hypertension controls included as follows: mild/moderate left ventricular outflow tract obstruction (7), mediastinal teratoma (1), portal vein stenosis (1).
INTERVENTIONS
Standard pulmonary arterial hypertension treatment.
MEASUREMENTS AND MAIN RESULTS
Analysis of differential concentrations (false discovery rate < 0.05) revealed two trans-right-ventricle microRNA gradients (pulmonary artery vs superior vena cava): miR-193a-5p (step-up in pulmonary arterial hypertension and step-down in control) and miR-423-5p (step-down in pulmonary arterial hypertension and step-up in control) and two transpulmonary microRNA gradients (ascending aorta vs pulmonary artery): miR-26b-5p (step-down only in control) and miR-331-3p (step-up only in pulmonary arterial hypertension). Between-group comparison revealed miR-29a-3p, miR-26a-5p, miR-590-5p, and miR-200c-3p as upregulated in pulmonary arterial hypertension-superior vena cava and miR-99a-5p as downregulated in pulmonary arterial hypertension-pulmonary artery. The differential microRNA-concentrations correlated with prognostic hemodynamic variables (pulmonary vascular resistance, tricuspid annular plane systolic excursion, etc.).
CONCLUSIONS
We identified for the first time in human disease (pulmonary arterial hypertension) trans-right-ventricle and transpulmonary microRNA gradients in blood plasma. Several of these microRNAs regulate transcripts that drive cardiac remodeling and pulmonary arterial hypertension and are now emerging as epigenetic pulmonary arterial hypertension biomarkers and targets for therapy.
Topics: Child; Familial Primary Pulmonary Hypertension; Heart Ventricles; Humans; MicroRNAs; Prospective Studies; Pulmonary Arterial Hypertension; Vena Cava, Superior
PubMed: 31876555
DOI: 10.1097/PCC.0000000000002207 -
Cancer Biomarkers : Section a of... 2022The potential of microRNAs (miRNAs) as molecular tumor biomarkers for early diagnosis and prognosis in lung cancer is still unclear.
BACKGROUND
The potential of microRNAs (miRNAs) as molecular tumor biomarkers for early diagnosis and prognosis in lung cancer is still unclear.
OBJECTIVE
To analyze expression of miRNAs in A549 lung adenocarcinoma (LUAD) cells and in primary, non-malignant bronchial epithelial (BE) cells from healthy donors. To analyze the most prominently deregulated miRNAs in plasma samples of LUAD patients and healthy donors.
MATERIALS AND METHODS
The expression of 752 miRNAs in LUAD and BE cells was assessed by RT-qPCR with mean-centering restricted normalization. The relative plasma levels of 18 miRNAs in LUAD patients and healthy donors were analyzed using RT-qPCR and normalized to miR-191-5p and miR-16-3p. Putative interactions between miRNAs and their target genes were investigated in silico.
RESULTS
Out of 752 miRNAs, 37 miRNAs were significantly deregulated in A549 cells compared to BE cells. MiR-15b-3p, miR-148a-3p, miR-193b-3p, and miR-195-5p were significantly deregulated in plasma samples of LUAD patients compared to donors. The target genes of those four miRNAs are involved in essential mechanisms in cancer development and progression.
CONCLUSIONS
There are substantial differences between cancer and control miRNA expression in vitro and in plasma samples of LUAD patients compared to healthy donors. Four deregulated miRNAs are promising as a diagnostic biomarker for adenocarcinoma of the lung.
Topics: Adenocarcinoma of Lung; Biomarkers, Tumor; Circulating MicroRNA; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MicroRNAs
PubMed: 35431230
DOI: 10.3233/CBM-210205 -
Molecular Oncology Mar 2016The role of circulating free microRNAs (cfmiRNAs) as promising tools for cancer screening, prognosis and monitoring of anticancer therapies has been widely studied in... (Review)
Review
The role of circulating free microRNAs (cfmiRNAs) as promising tools for cancer screening, prognosis and monitoring of anticancer therapies has been widely studied in the past decades. cfmiRNAs have all the characteristics of the perfect biomarkers owing high stability under storage and handling conditions and being detectable not only in plasma, but in almost all body fluids. Moreover, their levels in plasma are likely to resemble ones in the primary tumor. Recently, viral and plant miRNAs have been found in plasma of healthy individuals through deep sequencing technique, and subsequently the same ones were deregulated in patients. Growing body of literature is recently focusing on understanding the potential cross-kingdom regulation of human mRNAs by miRNAs most likely absorbed with food ingestion. In this article we will review the literature concerning the xenomiRs detected in plasma and their role in influencing cancer onset and progression. XenomiRs could potentially be used not only as early screening tool, but also for patients' prognosis.
Topics: Animals; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; RNA, Plant; RNA, Viral
PubMed: 26860056
DOI: 10.1016/j.molonc.2016.01.005