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miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 28650

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Special Issue Editors

Dr. Juan Gilabert-Estellés

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Guest Editor

1. Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Fundación Hospital General Universitario de Valencia, 46014 València, Spain
2. Comprehensive Multidisciplinary Endometriosis Unit, Consorcio Hospital General Universitario de Valencia, Valencia, Spain. Av. Tres Cruces, 46014 Valencia, Spain
3. Department of Paediatrics, Obstetrics and Gynaecology, University of Valencia, Valencia, Spain. Av. Blasco Ibáñez, 46010 Valencia, Spain
Interests: endometriosis; gynecological oncology; laparoscopy; minimally invasive surgery; robotic surgery; biomarkers
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Dr. Josep Marí-Alexandre

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Guest Editor

Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Fundación Hospital General Universitario de Valencia, 46014 València, Spain
Interests: endometriosis; gynecological oncology; miRNAs; epigenomics; biomarkers; translational research
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Prof. Dr. Martin Götte

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Guest Editor

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
Interests: endometriosis; gynecological oncology; microRNAs; stem cells; proteoglycans; extracellular matrix; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Personalized medicine has become a new paradigm for the management of a wide variety of diseases. A decisive factor for its development has been represented by the molecular characterization of tumours, paving the way for the development of risk stratification algorithms, biomarker development and targeted therapies.

miRNAs have attracted a greater interest in the last years as for the characterization of tumour biology. These small non-coding RNAs with regulatory properties have been proven to be deregulated in several pathologies, from benign pathologies as endometriosis or cardiovascular diseases to distinct forms of solid and haematological malignancies. Since a single miRNA might impact in multiple signalling pathways, they might be involved into disease pathophysiology and also might become potential therapeutic targets. Far from the classical miRNA mimic or antimiR approach, new evidences are pointing to targeted DNA methylation of miRNA promoters as a potential therapeutic strategy. Additionally, the discovery of miRNAs in a myriad of human biofluids has paved the way for its implementation as biomarkers of disease.

This Special Issue aims to broad the knowledge about current advances in the field of miRNAs as mechanisms of disease, biomarkers and potential therapeutic targets.

Dr. Juan Gilabert-Estellés
Dr. Josep Marí-Alexandre
Dr. Martin Götte
Guest Editors

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Keywords

miRNAs
Biomarkers
Therapeutics
Personalized medicine

Published Papers (9 papers)

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Editorial

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6 pages, 241 KiB

Open AccessEditorial

miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics

by Bárbara A. Mc Cormack, Eva González-Cantó, Cristina Agababyan, Nancy A. Espinoza-Sánchez, Sarai Tomás-Pérez, Antoni Llueca, Josep Marí-Alexandre, Martin Götte and Juan Gilabert-Estellés

Int. J. Mol. Sci. 2021, 22(15), 8154; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158154 - 29 Jul 2021

Cited by 4 | Viewed by 1866

Abstract

In recent years, interest in personalized medicine has considerably increased [...] Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

Research

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16 pages, 1647 KiB

Open AccessArticle

Identification of miR-20a-5p as Robust Normalizer for Urine microRNA Studies in Renal Cell Carcinoma and a Profile of Dysregulated microRNAs

by Julia Oto, Raquel Herranz, Emma Plana, José Vicente Sánchez-González, Javier Pérez-Ardavín, David Hervás, Álvaro Fernández-Pardo, Fernando Cana, César David Vera-Donoso, Manuel Martínez-Sarmiento and Pilar Medina

Int. J. Mol. Sci. 2021, 22(15), 7913; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157913 - 24 Jul 2021

Cited by 8 | Viewed by 1851

Abstract

Renal cell carcinoma (RCC) is the third most frequent urinary malignancy and one of the most lethal. Current diagnostic and follow-up techniques are harmful and unspecific in low-grade tumors. Novel minimally invasive markers such as urine microRNAs (miRNAs) are under study. However, discrepancies arise among studies in part due to lack of consent regarding normalization. We aimed to identify the best miRNA normalizer for RCC studies performed in urine samples together with a miRNA profile with diagnostic value and another for follow-up. We evaluated the performance of 120 candidate miRNAs in the urine of 16 RCC patients and 16 healthy controls by RT-qPCR followed by a stability analysis with RefFinder. In this screening stage, miR-20a-5p arose as the most stably expressed miRNA in RCC and controls, with a good expression level. Its stability was validated in an independent cohort of 51 RCC patients and 32 controls. Using miR-20a-5p as normalizer, we adjusted and validated a diagnostic model for RCC with three miRNAs (miR-200a-3p, miR-34a-5p and miR-365a-3p) (AUC = 0.65; Confidence Interval 95% [0.51, 0.79], p = 0.043). let-7d-5p and miR-205-5p were also upregulated in patients compared to controls. Comparing RCC samples before surgery and fourteen weeks after, we identified let-7d-5p, miR-152-3p, miR-30c-5p, miR-362-3p and miR-30e-3p as potential follow-up profile for RCC. We identified validated targets of most miRNAs in the renal cell carcinoma pathway. This is the first study that identifies a robust normalizer for urine RCC miRNA studies, miR-20a-5p, which may allow the comparison of future studies among laboratories. Once confirmed in a larger independent cohort, the miRNAs profiles identified may improve the non-invasive diagnosis and follow-up of RCC. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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27 pages, 3413 KiB

Open AccessArticle

Circulating Non-Coding RNAs as a Signature of Autism Spectrum Disorder Symptomatology

by Salam Salloum-Asfar, Ahmed K. Elsayed, Saba F. Elhag and Sara A. Abdulla

Int. J. Mol. Sci. 2021, 22(12), 6549; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126549 - 18 Jun 2021

Cited by 15 | Viewed by 3133

Abstract

Autism spectrum disorder (ASD) is a multifaced neurodevelopmental disorder that becomes apparent during early childhood development. The complexity of ASD makes clinically diagnosing the condition difficult. Consequently, by identifying the biomarkers associated with ASD severity and combining them with clinical diagnosis, one may better factionalize within the spectrum and devise more targeted therapeutic strategies. Currently, there are no reliable biomarkers that can be used for precise ASD diagnosis. Consequently, our pilot experimental cohort was subdivided into three groups: healthy controls, individuals those that express severe symptoms of ASD, and individuals that exhibit mild symptoms of ASD. Using next-generation sequencing, we were able to identify several circulating non-coding RNAs (cir-ncRNAs) in plasma. To the best of our knowledge, this study is the first to show that miRNAs, piRNAs, snoRNAs, Y-RNAs, tRNAs, and lncRNAs are stably expressed in plasma. Our data identify cir-ncRNAs that are specific to ASD. Furthermore, several of the identified cir-ncRNAs were explicitly associated with either the severe or mild groups. Hence, our findings suggest that cir-ncRNAs have the potential to be utilized as objective diagnostic biomarkers and clinical targets. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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15 pages, 5121 KiB

Open AccessArticle

Canonical and Interior Circular RNAs Function as Competing Endogenous RNAs in Psoriatic Skin

by Xiaoxin Liu, Jacqueline Frost, Anne Bowcock and Weixiong Zhang

Int. J. Mol. Sci. 2021, 22(10), 5182; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105182 - 13 May 2021

Cited by 10 | Viewed by 2217

Abstract

(1) Background: Understanding the function of circular RNAs (circRNAs), a class of noncoding RNA, in psoriatic skin can provide important insights into the complex regulation of genes contributing to the pathogenesis of psoriasis. (2) Methods: A novel method was applied to RNA-seq datasets from 93 skin biopsy samples to comprehensively identify circRNAs of all types, i.e., canonical circRNAs from the intron-exon junctions of mRNAs and interior circRNAs (i-circRNAs) from the interior regions of exons, introns, and intergenic regions. Selected circRNAs were experimentally validated by qRT-PCR and Sanger sequencing. CircRNAs with abundant and differential expression were identified and their putative function as competing endogenous RNAs (ceRNAs) was analyzed by an integrated analysis of circRNAs, microRNAs, and mRNAs. (3) Results: With a comprehensive search using no information of splicing signals, we systematically identified 179 highly abundant circRNAs in psoriatic skin. Many of these were reported for the first time and many were differentially expressed in involved versus normal or uninvolved skin. Validation based on three additional RNA-seq datasets confirmed most of the identified circRNAs in psoriatic skin. Experimental analyses confirmed the expression of the well-known circRNA CDR1as, a canonical circRNA, and a novel i-circRNA in psoriasis. We also identified many circRNAs that may act as ceRNAs to regulate the expression of mRNA genes in psoriasis-related signaling pathways in psoriasis. (4) Conclusions: The result of the study suggested that circRNAs are abundant in psoriatic skin, have distinct characteristics, and contribute to psoriatic pathogenesis. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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11 pages, 3523 KiB

Open AccessArticle

Circulating miRNAs Act as Diagnostic Biomarkers for Bladder Cancer in Urine

by Jen-Tai Lin and Kuo-Wang Tsai

Int. J. Mol. Sci. 2021, 22(8), 4278; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084278 - 20 Apr 2021

Cited by 23 | Viewed by 2429

Abstract

MicroRNAs (miRNAs) can be secreted into body fluids and have thus been reported as a new type of cancer biomarker. This study aimed to determine whether urinary miRNAs act as noninvasive biomarkers for diagnosing bladder cancer. Small RNA profiles from urine were generated for 10 patients with bladder cancer and 10 healthy controls by using next-generation sequencing. We identified 50 urinary miRNAs that were differentially expressed in bladder cancer compared with controls, comprising 44 upregulated and six downregulated miRNAs. Pathway enrichment analysis revealed that the biological role of these differentially expressed miRNAs might be involved in cancer-associated signaling pathways. Further analysis of the public database revealed that let-7b-5p, miR-149-5p, miR-146a-5p, miR-193a-5p, and miR-423-5p were significantly increased in bladder cancer compared with corresponding adjacent normal tissues. Furthermore, high miR-149-5p and miR-193a-5p expression was significantly correlated with poor overall survival in patients with bladder cancer. The qRT-PCR approach revealed that the expression levels of let-7b-5p, miR-149-5p, miR-146a-5p and miR-423-5p were significantly increased in the urine of patients with bladder cancer compared with those of controls. Although our results indicated that urinary miRNAs are promising biomarkers for diagnosing bladder cancer, this must be validated in larger cohorts in the future. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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18 pages, 3320 KiB

Open AccessArticle

The Status of EGFR Modulates the Effect of miRNA-200c on ZEB1 Expression and Cell Migration in Glioblastoma Cells

by Lisandra Muñoz-Hidalgo, Teresa San-Miguel, Javier Megías, Eva Serna, Silvia Calabuig-Fariñas, Daniel Monleón, Rosario Gil-Benso, Miguel Cerdá-Nicolás and Concha López-Ginés

Int. J. Mol. Sci. 2021, 22(1), 368; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010368 - 31 Dec 2020

Cited by 7 | Viewed by 2069

Abstract

Migration of glioblastoma cells into surrounding tissue is one of the main features that makes this tumor incurable. We evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns in 30 cases of primary glioblastoma. From the 64 miRNAs that showed differential expression between tumors with a high level of EGFR amplification and tumors without EGFR amplification, 40% were related with cell migration, being miR-200c the most differentially expressed between these two groups. We investigated the effect of miR-200c on ZEB1 expression and cell migration in an in vitro transfection model with a miR-200c mimic, a miR-200c inhibitor and siRNA targeting EGFR in three short-term cultures with different levels of EGFR amplification obtained from resected glioblastomas. The cell culture with the highest EGFR amplification level presented the lowest miR-200c expression and the status of EGFR modulated the effect of miR-200c on ZEB1 expression. Silencing EGFR led to miR-200c upregulation and ZEB1 downregulation in transfected cultures, except in the presence of high levels of EGFR. Likewise, miR-200c upregulation decreased ZEB1 expression and inhibited cell migration, especially when EGFR was not amplified. Our results suggest that modulating miR-200c may serve as a novel therapeutic approach for glioblastoma depending on EGFR status. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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Review

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15 pages, 1395 KiB

Open AccessReview

The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract

by Chiara De Santis and Martin Götte

Int. J. Mol. Sci. 2021, 22(14), 7359; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147359 - 08 Jul 2021

Cited by 12 | Viewed by 3697

Abstract

microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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23 pages, 1210 KiB

Open AccessReview

Epigenetic Regulation of microRNAs in Cancer: Shortening the Distance from Bench to Bedside

by María J. Pajares, Ester Alemany-Cosme, Saioa Goñi, Eva Bandres, Cora Palanca-Ballester and Juan Sandoval

Int. J. Mol. Sci. 2021, 22(14), 7350; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147350 - 08 Jul 2021

Cited by 36 | Viewed by 5419

Abstract

Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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30 pages, 722 KiB

Open AccessReview

Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases

by Chisato Kinoshita, Noriko Kubota and Koji Aoyama

Int. J. Mol. Sci. 2021, 22(10), 5292; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105292 - 18 May 2021

Cited by 21 | Viewed by 4248

Abstract

The number of patients with neurodegenerative diseases (NDs) is increasing, along with the growing number of older adults. This escalation threatens to create a medical and social crisis. NDs include a large spectrum of heterogeneous and multifactorial pathologies, such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and multiple system atrophy, and the formation of inclusion bodies resulting from protein misfolding and aggregation is a hallmark of these disorders. The proteinaceous components of the pathological inclusions include several RNA-binding proteins (RBPs), which play important roles in splicing, stability, transcription and translation. In addition, RBPs were shown to play a critical role in regulating miRNA biogenesis and metabolism. The dysfunction of both RBPs and miRNAs is often observed in several NDs. Thus, the data about the interplay among RBPs and miRNAs and their cooperation in brain functions would be important to know for better understanding NDs and the development of effective therapeutics. In this review, we focused on the connection between miRNAs, RBPs and neurodegenerative diseases. Full article

(This article belongs to the Special Issue miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics)

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