International Journal of Molecular Sciences

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14 pages, 4614 KiB

Open AccessArticle

Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer

by Alexandra Gherman, Loredana Balacescu, Calin Popa, Calin Cainap, Catalin Vlad, Simona S. Cainap and Ovidiu Balacescu

Int. J. Mol. Sci. 2023, 24(13), 10622; https://doi.org/10.3390/ijms241310622 - 25 Jun 2023

Cited by 6 | Viewed by 1697

Abstract

The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic [...] Read more.

The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic colorectal cancer patients were selected before receiving first-line irinotecan- or oxaliplatin-based chemotherapy. Blood samples were harvested at baseline and 4–6 months after the initiation of chemotherapy. The levels of exosomal expression for each miRNA were analyzed by qPCR. Our results for patients receiving first-line FOLFOX showed significantly higher baseline levels of miR-92a-3p (p = 0.007 **), miR-146a-5p (p = 0.036 *), miR-221-3p (p = 0.047 *), and miR-484 (p = 0.009 **) in non-responders (NR) vs. responders (R). Of these, miR-92a-3p (AUC = 0.735), miR-221-3p (AUC = 0.774), and miR-484 (AUC = 0.725) demonstrated a predictive ability to discriminate responses from non-responses, regardless of the therapy used. Moreover, Cox regression analysis indicated that higher expression levels of miR-92a-3p (p = 0.008 **), miR-143-3p (p = 0.009 **), miR-221-3p (p = 0.016 *), and miR-486-5p (p = 0.019 *) at baseline were associated with worse overall survival, while patients expressing higher baseline miR-92a-3p (p = 0.003 **) and miR-486-5p (p = 0.003 **) had lower rates of progression-free survival. No predictive values for candidate microRNAs were found for the post-chemotherapy period. In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions. Full article

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

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15 pages, 2513 KiB

Open AccessArticle

Effect of ZEB1 Associated with microRNAs on Tumor Stem Cells in Head and Neck Cancer

by Letícia Antunes Muniz Ferreira, Maria Antonia dos Santos Bezerra, Rosa Sayoko Kawasaki-Oyama, Glaucia Maria de Mendonça Fernandes, Márcia Maria Urbanin Castanhole-Nunes, Vilson Serafim Junior, Rogério Moraes Castilho, Érika Cristina Pavarino, José Victor Maniglia and Eny Maria Goloni-Bertollo

Int. J. Mol. Sci. 2023, 24(6), 5916; https://doi.org/10.3390/ijms24065916 - 21 Mar 2023

Cited by 3 | Viewed by 2254

Abstract

Cancer biologists have focused on studying cancer stem cells (CSCs) because of their ability to self-renew and recapitulate tumor heterogeneity, which increases their resistance to chemotherapy and is associated with cancer relapse. Here, we used two approaches to isolate CSCs: the first involved [...] Read more.

Cancer biologists have focused on studying cancer stem cells (CSCs) because of their ability to self-renew and recapitulate tumor heterogeneity, which increases their resistance to chemotherapy and is associated with cancer relapse. Here, we used two approaches to isolate CSCs: the first involved the metabolic enzyme aldehyde dehydrogenase ALDH, and the second involved the three cell surface markers CD44, CD117, and CD133. ALDH cells showed a higher zinc finger E-box binding homeobox 1 (ZEB1) microRNA (miRNA) expression than CD44/CD117/133 triple-positive cells, which overexpressed miRNA 200c-3p: a well-known microRNA ZEB1 inhibitor. We found that ZEB1 inhibition was driven by miR-101-3p, miR-139-5p, miR-144-3p, miR-199b-5p, and miR-200c-3p and that the FaDu Cell Line inhibition occurred at the mRNA level, whereas HN13 did not affect mRNA expression but decreased protein levels. Furthermore, we demonstrated the ability of the ZEB1 inhibitor miRNAs to modulate CSC-related genes, such as TrkB, ALDH, NANOG, and HIF1A, using transfection technology. We showed that ALDH was upregulated upon ZEB1-suppressed miRNA transfection (Mann–Whitney ** p₁₀₁ = 0.009, t-test ** p₁₃₉ = 0.009, t-test ** p₁₄₄ = 0.002, and t-test *** p₁₉₉ = 0.0006). Overall, our study enabled an improved understanding of the role of ZEB1-suppressed miRNAs in CSC biology. Full article

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

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14 pages, 3472 KiB

Open AccessArticle

miR-210 Expression Is Strongly Hypoxia-Induced in Anaplastic Thyroid Cancer Cell Lines and Is Associated with Extracellular Vesicles and Argonaute-2

by Bonita H. Powell, Andrey Turchinovich, Yongchun Wang, Olesia Gololobova, Dominik Buschmann, Martha A. Zeiger, Christopher B. Umbricht and Kenneth W. Witwer

Int. J. Mol. Sci. 2023, 24(5), 4507; https://doi.org/10.3390/ijms24054507 - 24 Feb 2023

Cited by 6 | Viewed by 2388

Abstract

Hypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating [...] Read more.

Hypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating aggressive cancers. Here, we explore the potential of the well-known hypoxia-responsive microRNA (miRNA) miR-210-3p as a cellular and extracellular biological marker of hypoxia. We compare miRNA expression across several ATC and papillary thyroid cancer (PTC) cell lines. In the ATC cell line SW1736, miR-210-3p expression levels indicate hypoxia during exposure to low oxygen conditions (2% O₂). Furthermore, when released by SW1736 cells into the extracellular space, miR-210-3p is associated with RNA carriers such as extracellular vesicles (EVs) and Argonaute-2 (AGO2), making it a potential extracellular marker for hypoxia. Full article

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

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16 pages, 2782 KiB

Open AccessArticle

MiR-182 Is Upregulated in Prostate Cancer and Contributes to Tumor Progression by Targeting MITF

by M. Y. Cynthia Stafford and Declan J. McKenna

Int. J. Mol. Sci. 2023, 24(3), 1824; https://doi.org/10.3390/ijms24031824 - 17 Jan 2023

Cited by 10 | Viewed by 2563

Abstract

Altered expression of microRNA-182-5p (miR-182) has been consistently linked with many cancers, but its specific role in prostate cancer remains unclear. In particular, its contribution to epithelial–to–mesenchymal transition (EMT) in this setting has not been well studied. Therefore, this paper profiles the expression [...] Read more.

Altered expression of microRNA-182-5p (miR-182) has been consistently linked with many cancers, but its specific role in prostate cancer remains unclear. In particular, its contribution to epithelial–to–mesenchymal transition (EMT) in this setting has not been well studied. Therefore, this paper profiles the expression of miR-182 in prostate cancer and investigates how it may contribute to progression of this disease. In vitro experiments on prostate cancer cell lines and in silico analyses of The Cancer Genome Atlas (TCGA) prostate adenocarcinoma (PRAD) datasets were performed. PCR revealed miR-182 expression was significantly increased in prostate cancer cell lines compared to normal prostate cells. Bioinformatic analysis of TCGA PRAD data similarly showed upregulation of miR-182 was significantly associated with prostate cancer and clinical markers of disease progression. Functional enrichment analysis confirmed a significant association of miR-182 and its target genes with EMT. The EMT-linked gene MITF (melanocyte inducing transcription factor) was subsequently shown to be a novel target of miR-182 in prostate cancer cells. Further TCGA analysis suggested miR-182 expression can be an indicator of patient outcomes and disease progression following therapy. In summary, this is the first study to report that miR-182 over-expression in prostate cancer may contribute to EMT by targeting MITF expression. We propose miR-182 as a potentially useful diagnostic and prognostic biomarker for prostate cancer and other malignancies. Full article

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

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14 pages, 2667 KiB

Open AccessArticle

Analysis of Differentially Expressed MicroRNAs in Serum and Lung Tissues from Individuals with Severe Asthma Treated with Oral Glucocorticoids

by Marta Gil-Martínez, Clara Lorente-Sorolla, José M. Rodrigo-Muñoz, Miguel Ángel Lendínez, Gonzalo Núñez-Moreno, Lorena de la Fuente, Pablo Mínguez, Ignacio Mahíllo-Fernández, Joaquín Sastre, Marcela Valverde-Monge, Santiago Quirce, María L. Caballero, Francisco J. González-Barcala, Ebymar Arismendi, Irina Bobolea, Antonio Valero, Xavier Muñoz, María Jesús Cruz, Carlos Martínez-Rivera, Vicente Plaza, José M. Olaguibel and Victoria del Pozo Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(2), 1611; https://doi.org/10.3390/ijms24021611 - 13 Jan 2023

Cited by 5 | Viewed by 2121

Abstract

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients [...] Read more.

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV₁/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment. Full article

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

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10 pages, 2202 KiB

Open AccessArticle

Downexpression of miR-200c-3p Contributes to Achalasia Disease by Targeting the PRKG1 Gene

by Lucia Micale, Carmela Fusco, Grazia Nardella, Orazio Palmieri, Tiziana Latiano, Domenica Gioffreda, Francesca Tavano, Anna Panza, Antonio Merla, Giuseppe Biscaglia, Marco Gentile, Antonello Cuttitta, Marco Castori, Francesco Perri and Anna Latiano

Int. J. Mol. Sci. 2023, 24(1), 668; https://doi.org/10.3390/ijms24010668 - 30 Dec 2022

Cited by 2 | Viewed by 2408

Abstract

Achalasia is an esophageal smooth muscle motility disorder with unknown pathogenesis. Taking into account our previous results on the downexpression of miR-200c-3p in tissues of patients with achalasia correlated with an increased expression of PRKG1, SULF1, and SYDE1 genes, our aim [...] Read more.

Achalasia is an esophageal smooth muscle motility disorder with unknown pathogenesis. Taking into account our previous results on the downexpression of miR-200c-3p in tissues of patients with achalasia correlated with an increased expression of PRKG1, SULF1, and SYDE1 genes, our aim was to explore the unknown biological interaction between these genes and human miR-200c-3p and if this relation could unravel their functional role in the etiology of achalasia. To search for putative miR-200c-3p binding sites in the 3′-UTR of PRKG1, SULF1 and SYDE1, a bioinformatics tool was used. To test whether PRKG1, SULF1, and SYDE1 are targeted by miR-200c-3p, a dual-luciferase reporter assay and quantitative PCR on HEK293 and fibroblast cell lines were performed. To explore the biological correlation between PRKG1 and miR-200c-3p, an immunoblot analysis was carried out. The overexpression of miR-200c-3p reduced the luciferase activity in cells transfected with a luciferase reporter containing a fragment of the 3′-UTR regions of PRKG1, SULF1, and SYDE1 which included the miR-200c-3p seed sequence. The deletion of the miR-200c-3p seed sequence from the 3′-UTR fragments abrogated this reduction. A negative correlation between miR-200c-3p and PRKG1, SULF1, and SYDE1 expression levels was observed. Finally, a reduction of the endogenous level of PRKG1 in cells overexpressing miR-200c-3p was detected. Our study provides, for the first time, functional evidence about the PRKG1 gene as a direct target and SULF1 and SYDE1 as potential indirect substrates of miR-200c-3p and suggests the involvement of NO/cGMP/PKG signaling in the pathogenesis of achalasia. Full article

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

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17 pages, 5953 KiB

Open AccessArticle

Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature

by Georgios Tsakonas, Andreas Koulouris, Dominika Kazmierczak, Johan Botling, Cristian Ortiz-Villalon, Helena Nord, Magnus Lindskog, Martin Sandelin, Patrick Micke, Per Hydbring and Simon Ekman

Int. J. Mol. Sci. 2023, 24(1), 193; https://doi.org/10.3390/ijms24010193 - 22 Dec 2022

Cited by 5 | Viewed by 3307

Abstract

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth [...] Read more.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections. Full article

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

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20 pages, 868 KiB

Open AccessArticle

Circulating Small EVs miRNAs as Predictors of Pathological Response to Neo-Adjuvant Therapy in Breast Cancer Patients

by Oana Baldasici, Loredana Balacescu, Daniel Cruceriu, Andrei Roman, Carmen Lisencu, Bogdan Fetica, Simona Visan, Andrei Cismaru, Ancuta Jurj, Lucian Barbu-Tudoran, Valentina Pileczki, Laurian Vlase, Oana Tudoran and Ovidiu Balacescu

Int. J. Mol. Sci. 2022, 23(20), 12625; https://doi.org/10.3390/ijms232012625 - 20 Oct 2022

Cited by 15 | Viewed by 2688

Abstract

Neo-adjuvant therapy (NAT) is increasingly used in the clinic for the treatment of breast cancer (BC). Pathological response to NAT has been associated with improved patients’ survival; however, the current techniques employed for assessing the tumor response have significant limitations. Small EVs (sEVs)-encapsulated [...] Read more.

Neo-adjuvant therapy (NAT) is increasingly used in the clinic for the treatment of breast cancer (BC). Pathological response to NAT has been associated with improved patients’ survival; however, the current techniques employed for assessing the tumor response have significant limitations. Small EVs (sEVs)-encapsulated miRNAs have emerged as promising new biomarkers for diagnosis and prediction. Therefore, our study aims to explore the predictive value of these miRNAs for the pathological response to NAT in BC. By employing bioinformatic tools, we selected a set of miRNAs and evaluated their expression in plasma sEVs and BC biopsies. Twelve miRNAs were identified in sEVs, of which, miR-21-5p, 221-3p, 146a-5p and 26a-5p were significantly associated with the Miller–Payne (MP) pathological response to NAT. Moreover, miR-21-5p, 146a-5p, 26a-5p and miR-24-3p were independent as predictors of MP response to NAT. However, the expression of these miRNAs showed no correlation between sEVs and tissue samples, indicating that the mechanisms of miRNA sorting into sEVs still needs to be elucidated. Functional analysis of miRNA target genes and drug interactions revealed that candidate miRNAs and their targets, can be regulated by different NAT regimens. This evidence supports their role in governing the patients’ therapy response and highlights their potential use as prediction biomarkers. Full article

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

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13 pages, 1483 KiB

Open AccessArticle

Quantitative Prediction of Steatosis in Patients with Non-Alcoholic Fatty Liver by Means of Hepatic MicroRNAs Present in Serum and Correlating with Hepatic Fat

by Guillermo Quintás, Florian Caiment, Iván Rienda, Judith Pérez-Rojas, Eugenia Pareja, José V. Castell and Ramiro Jover

Int. J. Mol. Sci. 2022, 23(16), 9298; https://doi.org/10.3390/ijms23169298 - 18 Aug 2022

Cited by 3 | Viewed by 2018

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide, but a reliable non-invasive method to quantify liver steatosis in primary healthcare is not available. Circulating microRNAs have been proposed as biomarkers of severe/advanced NAFLD (steatohepatitis and fibrosis). [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide, but a reliable non-invasive method to quantify liver steatosis in primary healthcare is not available. Circulating microRNAs have been proposed as biomarkers of severe/advanced NAFLD (steatohepatitis and fibrosis). However, the use of circulating miRNAs to quantitatively assess the % of liver fat in suspected NAFLD patients has not been investigated. We performed global miRNA sequencing in two sets of samples: human livers from organ donors (n = 20), and human sera from biopsy-proven NAFLD patients (n = 23), both with a wide range of steatosis quantified in their liver biopsies. Partial least squares (PLS) regression combined with recursive feature elimination (RFE) was used to select miRNAs associated with steatosis. Moreover, regression models with only 2 or 3 miRNAs, with high biological relevance, were built. Comprehensive microRNA sequencing of liver and serum samples resulted in two sets of abundantly expressed miRNAs (418 in liver and 351 in serum). Pearson correlation analyses indicated that 18% of miRNAs in liver and 14.5% in serum were significantly associated with the amount of liver fat. PLS-RFE models demonstrated that 50 was the number of miRNAs providing the lowest error in both liver and serum models predicting steatosis. Comparison of the two miRNA subsets showed 19 coincident miRNAs that were ranked according to biological significance (guide/passenger strand, relative abundance in liver and serum, number of predicted lipid metabolism target genes, correlation significance, etc.). Among them, miR-10a-5p, miR-98-5p, miR-19a-3p, miR-30e-5p, miR-32-5p and miR-145-5p showed the highest biological relevance. PLS regression models with serum levels of 2–3 of these miRNAs predicted the % of liver fat with errors <5%. Full article

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

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11 pages, 2038 KiB

Open AccessArticle

The Relationship and Expression of miR-451a, miR-25-3p and PTEN in Early Peritoneal Endometriotic Lesions and Their Modulation In Vitro

by Warren B. Nothnick, Riley Peterson, Paige Minchella, Tommaso Falcone, Amanda Graham and Austin Findley

Int. J. Mol. Sci. 2022, 23(11), 5862; https://doi.org/10.3390/ijms23115862 - 24 May 2022

Cited by 2 | Viewed by 2049

Abstract

Background: miR-451a can function as a tumor suppresser and has been shown to be elevated in both endometriotic lesion tissue and serum from women with endometriosis. To further explore the role of miR-451a in the pathophysiology of endometriosis, specifically, further evaluating its association [...] Read more.

Background: miR-451a can function as a tumor suppresser and has been shown to be elevated in both endometriotic lesion tissue and serum from women with endometriosis. To further explore the role of miR-451a in the pathophysiology of endometriosis, specifically, further evaluating its association with the tumor suppressor, phosphatase and tensin homolog (PTEN), we examined their expression in individual endometriotic lesion tissue to gain insight into their relationship and further explore if miR-451a regulates PTEN expression. Methods: A total of 55 red, peritoneal endometriotic lesions and matched eutopic endometrial specimens were obtained from 46 patients with endometriosis. miR-451a, miR-25-3p and PTEN mRNA levels were assessed by qRT-PCR and reported for each matched eutopic and ectopic sample. To evaluate miR-451a and miR-25-3p expression of miR-25-3p and PTEN, respectively, 12Z cells (endometriotic epithelial cell line) were transfected and miR-25-3p expression was assessed by qRT-PCR, while PTEN protein expression was assessed by Western blotting. Results: PTEN and miR-25-3p expression exhibited an inverse relationship, as did miR-25-3p and miR-451a in individual lesions. Over-expression of miR-451a in 12Z cells resulted in down-regulation of miR-25-3p, while up-regulation of miR-25-3p resulted in down-regulation of PTEN protein expression. Conclusions: By assessing individual endometriotic lesion expression, we discovered an inverse relationship between miR-451a, miR-25-3p and PTEN, while in vitro cell transfection studies suggest that miR-451a may regulate PTEN expression via modulating miR-25-3p. Full article

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

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16 pages, 2930 KiB

Open AccessArticle

MicroRNAs in Leukemias: A Clinically Annotated Compendium

by Aleksander Turk, George A. Calin and Tanja Kunej

Int. J. Mol. Sci. 2022, 23(7), 3469; https://doi.org/10.3390/ijms23073469 - 23 Mar 2022

Cited by 11 | Viewed by 2886

Abstract

Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class [...] Read more.

Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class of short, noncoding RNAs responsible for epigenetic regulation of gene expression and have been proposed as a source of potential novel therapeutic targets for leukemias. In order to identify central miRNAs for leukemia, we conducted data synthesis using two databases: miRTarBase and DISNOR. A total of 137 unique miRNAs associated with 16 types of leukemia were retrieved from miRTarBase and 86 protein-coding genes associated with leukemia were retrieved from the DISNOR database. Based on these data, we formed a visual network of 248 miRNA-target interactions (MTI) between leukemia-associated genes and miRNAs associated with ≥4 leukemia types. We then manually reviewed the literature describing these 248 MTIs for interactions identified in leukemia studies. This manually curated data was then used to visualize a network of 64 MTIs identified in leukemia patients, cell lines and animal models. We also formed a visual network of miRNA-leukemia associations. Finally, we compiled leukemia clinical trials from the ClinicalTrials database. miRNAs with the highest number of MTIs were miR-125b-5p, miR-155-5p, miR-181a-5p and miR-19a-3p, while target genes with the highest number of MTIs were TP53, BCL2, KIT, ATM, RUNX1 and ABL1. The analysis of 248 MTIs revealed a large, highly interconnected network. Additionally, a large MTI subnetwork was present in the network visualized from manually reviewed data. The interconnectedness of the MTI subnetwork suggests that certain miRNAs represent central disease molecules for multiple leukemia types. Additional studies on miRNAs, their target genes and associated biological pathways are required to elucidate the therapeutic potential of miRNAs in leukemia. Full article

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

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15 pages, 2581 KiB

Open AccessArticle

Identification of Novel Circulating miRNAs in Patients with Acute Ischemic Stroke

by Eman K. Aldous, Salman M. Toor, Aijaz Parray, Yasser Al-Sarraj, Ilhame Diboun, Essam M. Abdelalim, Abdelilah Arredouani, Omar El-Agnaf, Paul J. Thornalley, Naveed Akhtar, Sajitha V. Pananchikkal, Ashfaq Shuaib, Nehad M. Alajez and Omar M. E. Albagha

Int. J. Mol. Sci. 2022, 23(6), 3387; https://doi.org/10.3390/ijms23063387 - 21 Mar 2022

Cited by 16 | Viewed by 4100

Abstract

Ischemic strokes are associated with significant morbidity and mortality, but currently there are no reliable prognostic or diagnostic blood biomarkers. MicroRNAs (miRNAs) regulate various molecular pathways and may be used as biomarkers. Using RNA-Seq, we conducted comprehensive circulating miRNA profiling in patients with [...] Read more.

Ischemic strokes are associated with significant morbidity and mortality, but currently there are no reliable prognostic or diagnostic blood biomarkers. MicroRNAs (miRNAs) regulate various molecular pathways and may be used as biomarkers. Using RNA-Seq, we conducted comprehensive circulating miRNA profiling in patients with ischemic stroke compared with healthy controls. Samples were collected within 24 h of clinical diagnosis. Stringent analysis criteria of discovery (46 cases and 95 controls) and validation (47 cases and 96 controls) cohorts led to the identification of 10 differentially regulated miRNAs, including 5 novel miRNAs, with potential diagnostic significance. Hsa-miR-451a was the most significantly upregulated miRNA (FC; 4.8, FDR; 3.78 × 10⁻⁸⁵), while downregulated miRNAs included hsa-miR-574-5p and hsa-miR-142-3p, among others. Importantly, we computed a multivariate classifier based on the identified miRNA panel to differentiate between ischemic stroke patients and healthy controls, which showed remarkably high sensitivity (0.94) and specificity (0.99). The area under the ROC curve was 0.97 and it is superior to other current available biomarkers. Moreover, in samples collected one month following stroke, we found sustained upregulation of hsa-miR-451a and downregulation of another 5 miRNAs. Lastly, we report 3 miRNAs that were significantly associated with poor clinical outcomes of stroke, as defined by the modified Rankin scores. The clinical translation of the identified miRNA panel may be explored further. Full article

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

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13 pages, 2165 KiB

Open AccessArticle

MiRNA-29b and miRNA-497 Modulate the Expression of Carboxypeptidase X Member 2, a Candidate Gene Associated with Left Ventricular Hypertrophy

by Jana Subrova, Karen Böhme, Allan Gillespie, Miriam Orphal, Claudia Plum, Reinhold Kreutz and Andreas Eisenreich

Int. J. Mol. Sci. 2022, 23(4), 2263; https://doi.org/10.3390/ijms23042263 - 18 Feb 2022

Cited by 3 | Viewed by 2494

Abstract

Left ventricular hypertrophy (LVH) is a major risk factor for adverse cardiovascular events. Recently, a novel candidate gene encoding the carboxypeptidase X member 2 (CPXM2) was found to be associated with hypertension-induced LVH. CPXM2 belongs to the M14 family of metallocarboxypeptidases, yet it [...] Read more.

Left ventricular hypertrophy (LVH) is a major risk factor for adverse cardiovascular events. Recently, a novel candidate gene encoding the carboxypeptidase X member 2 (CPXM2) was found to be associated with hypertension-induced LVH. CPXM2 belongs to the M14 family of metallocarboxypeptidases, yet it lacks detectable enzyme activity, and its function remains unknown. Here, we investigated the impact of micro (mi)RNA-29b, miRNA-195, and miRNA-497 on the posttranscriptional expression control of CPXM2. Candidate miRNAs for CPXM2 expression control were identified in silico. CPXM2 expression in rat cardiomyocytes (H9C2) was characterized via real-time PCR, Western blotting, and immunofluorescence. Direct miRNA/target mRNA interaction was analysed by dual luciferase assay. CPXM2 was expressed in H9C2 and co-localised with z-disc associated protein PDZ and LIM domain 3 (Pdlim3). Transfection of H9C2 with miRNA-29b, miRNA-195, and miRNA-497 led to decreased levels of CPXM2 mRNA and protein, respectively. Results of dual luciferase assays revealed that miRNA-29b and miRNA-497, but not miRNA-195, directly regulated CPXM2 expression on a posttranscriptional level via binding to the 3′UTR of CPXM2 mRNA. We identified two miRNAs capable of the direct posttranscriptional expression control of CPXM2 expression in rat cardiomyocytes. This novel data may help to shed more light on the—so far—widely unexplored expression control of CPXM2 and its potential role in LVH. Full article

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

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Review

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16 pages, 9471 KiB

Open AccessReview

Advances and Highlights of miRNAs in Asthma: Biomarkers for Diagnosis and Treatment

by Marta Gil-Martínez, Clara Lorente-Sorolla, Sara Naharro, José M. Rodrigo-Muñoz and Victoria del Pozo

Int. J. Mol. Sci. 2023, 24(2), 1628; https://doi.org/10.3390/ijms24021628 - 13 Jan 2023

Cited by 10 | Viewed by 3253

Abstract

Asthma is a heterogeneous inflammatory disease of the airways that causes breathing difficulties, episodes of cough and wheezing, and in more severe cases can greatly diminish quality of life. Epigenetic regulation, including post-transcriptional mediation of microRNAs (miRNAs), is one of the mechanisms behind [...] Read more.

Asthma is a heterogeneous inflammatory disease of the airways that causes breathing difficulties, episodes of cough and wheezing, and in more severe cases can greatly diminish quality of life. Epigenetic regulation, including post-transcriptional mediation of microRNAs (miRNAs), is one of the mechanisms behind the development of the range of asthma phenotypes and endotypes. As in every other immune-mediated disease, miRNAs regulate the behavior of cells that shape the airway structure as well as those in charge of the defense mechanisms in the bronchi and lungs, controlling cell survival, growth, proliferation, and the ability of cells to synthesize and secrete chemokines and immune mediators. More importantly, miRNAs are molecules with chemical and biological properties that make them appropriate biomarkers for disease, enabling stratification of patients for optimal drug selection and thereby simplifying clinical management and reducing both the economic burden and need for critical care associated with the disease. In this review, we summarize the roles of miRNAs in asthma and describe how they regulate the mechanisms of the disease. We further describe the current state of miRNAs as biomarkers for asthma phenotyping, endotyping, and treatment selection. Full article

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

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14 pages, 1254 KiB

Open AccessReview

miRNA Pathway Alteration in Response to Non-Coding RNA Delivery in Viral Vector-Based Gene Therapy

by Darya A. Savenkova, Aelita-Luiza A. Makarova, Igor K. Shalik and Dmitry V. Yudkin

Int. J. Mol. Sci. 2022, 23(23), 14954; https://doi.org/10.3390/ijms232314954 - 29 Nov 2022

Cited by 7 | Viewed by 2818

Abstract

Gene therapy is widely used to treat incurable disorders and has become a routine procedure in clinical practice. Since viruses can exhibit specific tropisms, effectively penetrate the cell, and are easy to use, most gene therapy approaches are based on viral delivery of [...] Read more.

Gene therapy is widely used to treat incurable disorders and has become a routine procedure in clinical practice. Since viruses can exhibit specific tropisms, effectively penetrate the cell, and are easy to use, most gene therapy approaches are based on viral delivery of genetic material. However, viral vectors have some disadvantages, such as immune response and cytotoxicity induced by a disturbance of cell metabolism, including miRNA pathways that are an important part of transcription regulation. Therefore, any viral-based gene therapy approach involves the evaluation of side effects and safety. It is possible for such effects to be caused either by the viral vectors themselves or by the delivered genetic material. Many gene therapy techniques use non-coding RNA delivery as an effective agent for gene expression regulation, with the risk of cellular miRNA pathways being affected due to the nature of the non-coding RNAs. This review describes the effect of viral vector entry and non-coding RNA delivery by these vectors on miRNA signaling pathways. Full article

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

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14 pages, 771 KiB

Open AccessReview

Systematic Review of the Diagnostic and Clinical Utility of Salivary microRNAs in Traumatic Brain Injury (TBI)

by Matthew I. Hiskens, Tesfaye S. Mengistu, Katy M. Li and Andrew S. Fenning

Int. J. Mol. Sci. 2022, 23(21), 13160; https://doi.org/10.3390/ijms232113160 - 29 Oct 2022

Cited by 11 | Viewed by 3082

Abstract

Research in traumatic brain injury (TBI) is an urgent priority, as there are currently no TBI biomarkers to assess the severity of injury, to predict outcomes, and to monitor recovery. Small non-coding RNAs (sncRNAs) including microRNAs can be measured in saliva following TBI [...] Read more.

Research in traumatic brain injury (TBI) is an urgent priority, as there are currently no TBI biomarkers to assess the severity of injury, to predict outcomes, and to monitor recovery. Small non-coding RNAs (sncRNAs) including microRNAs can be measured in saliva following TBI and have been investigated as potential diagnostic markers. The aim of this systematic review was to investigate the diagnostic or prognostic ability of microRNAs extracted from saliva in human subjects. PubMed, Embase, Scopus, PsycINFO and Web of Science were searched for studies that examined the association of saliva microRNAs in TBI. Original studies of any design involving diagnostic capacity of salivary microRNAs for TBI were selected for data extraction. Nine studies met inclusion criteria, with a heterogeneous population involving athletes and hospital patients, children and adults. The studies identified a total of 188 differentially expressed microRNAs, with 30 detected in multiple studies. MicroRNAs in multiple studies involved expression change bidirectionality. The study design and methods involved significant heterogeneity that precluded meta-analysis. Early data indicates salivary microRNAs may assist with TBI diagnosis. Further research with consistent methods and larger patient populations is required to evaluate the diagnostic and prognostic potential of saliva microRNAs. Full article

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

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