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Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition

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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: 20 January 2025 | Viewed by 14614

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Prof. Dr. Kyriacos N. Felekkis

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Non-Coding RNA Research Laboratory, Department of Life Sciences, School of Life and Health Sciences, University of Nicosia, 2417 Nicosia, Cyprus
Interests: non-coding RNAs; miRNAs; biomarkers; personalized medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Christos Papaneophytou

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Department of Life Sciences, School of Life and Health Sciences, University of Nicosia, Nicosia 2417, Cyprus
Interests: drug development; small-molecule inhibitors; miRNAs; antimicrobial compounds
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Circulating non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and PIWI-interacting RNAs, are a class of stable RNAs that do not encode proteins, which can be detected in body fluids, including blood and urine. Several ncRNAs regulate several cellular functions, such as proliferation, apoptosis, and cell cycle progression. NcRNAs have been reported to contribute at various levels of disease pathogenesis, ranging from causative players to modifying factors. Inevitably, their role in human diseases has become apparent. Additionally, emphasis has been given to the role of these molecules as diagnostic, prognostic, and even therapeutic biomarkers of human diseases. Despite the initial difficulties on that front, due to the high intra- and intervariability, many of these discoveries are currently reaching the clinic. In the era of personalized medicine, elucidating the multifaceted role of ncRNAs in human diseases is considered of utmost importance.

This Special Issue invites submissions of original papers and reviews that cover recent advances in the application of ncRNAs as prognostic and diagnostic biomarkers of human diseases and other related subjects.

Prof. Dr. Kyriacos N. Felekkis
Dr. Christos Papaneophytou
Guest Editors

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Keywords

miRNA
gene expression regulation
diagnosis
prognosis
therapy
biomarkers

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Research

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22 pages, 1628 KiB

Open AccessArticle

Plasma microRNAs Associate Positive, Negative, and Cognitive Symptoms with Inflammation in Schizophrenia

by Takuya Miyano, Masakazu Hirouchi, Naoki Yoshimura, Kotaro Hattori, Tsuyoshi Mikkaichi and Naoki Kiyosawa

Int. J. Mol. Sci. 2024, 25(24), 13522; https://doi.org/10.3390/ijms252413522 - 17 Dec 2024

Viewed by 237

Abstract

Schizophrenia is a complex and heterogenous psychiatric disorder characterized by positive, negative, and cognitive symptoms. Our previous study identified three subgroups of schizophrenia patients based on plasma microRNA (miRNA) profiles. The present study aims to (1) verify the reproducibility of the miRNA-based patient stratification and (2) explore the pathophysiological pathways linked to the symptoms using plasma miRNAs. We measured levels of 376 miRNAs in plasma samples of schizophrenia patients and obtained their Positive and Negative Syndrome Scale (PANSS) scores and the Brief Assessment of Cognition in Schizophrenia (BACS) scores. The plasma miRNA profiles identified similar subgroups of patients as in the previous study, suggesting miRNA-based patient stratification is potentially reproducible. Our multivariate analysis identified optimal combinations of miRNAs to estimate the PANSS positive and negative subscales and BACS composite scores. Those miRNAs consistently enriched ‘inflammation’ and ‘NFκB1′ according to miRNA set enrichment analysis. Our literature-based text mining and survey confirmed that those miRNAs were associated with IL-1β, IL-6, and TNFα, suggesting that exacerbated positive, negative, and cognitive symptoms are associated with high inflammation. In conclusion, miRNAs are a potential biomarker to identify patient subgroups reflecting pathophysiological conditions and to investigate symptom-related molecular mechanisms in schizophrenia. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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15 pages, 1702 KiB

Open AccessArticle

Circulating miR-23b-3p, miR-30e-3p, and miR-205-5p as Novel Predictive Biomarkers for Ramucirumab–Paclitaxel Therapy Outcomes in Advanced Gastric Cancer

by Emanuele Piccinno, Annalisa Schirizzi, Viviana Scalavino, Giampiero De Leonardis, Rossella Donghia, Alessia Fantasia, Angela Dalia Ricci, Claudio Lotesoriere, Gianluigi Giannelli, Grazia Serino and Rosalba D’Alessandro

Int. J. Mol. Sci. 2024, 25(24), 13498; https://doi.org/10.3390/ijms252413498 - 17 Dec 2024

Viewed by 182

Abstract

Angiogenesis inhibition treatments are limited and are often too late for advanced gastric cancer (GC) patients, in whom its efficacy is reduced. New molecular biomarkers are needed to optimize therapy regimens. In regard to this framework, circulating miRNAs, with high sensitivity and specificity, could be useful biomarkers of GC. The present longitudinal study was focused on analyzing the expression levels of a blood miRNA signature in a cohort of 40 patients receiving second-line therapy combining Ramucirumab and Paclitaxel, stratified based on their Progression-Free Survival (PFS). Using differential and bioinformatic analysis, miR-205-5p, miR-30e-3p, and miR-23b-3p were selected as possible predictive biomarkers, with the results showing that they were more highly expressed in patients exhibiting longer PFS and that they were involved in modulating angiogenesis. Furthermore, patients with longer PFS showed a progressive and significant decrease in the selected miRNA to minimal levels. The loss of the protective effect and the increased expression of the hypothetical targets, including angiopoietin-2, were then observed. The hypothesis was supported by the inverse correlation found for miR-205-5p and angiopoietin-2. Circulating levels of miR-205-5p were protective (HR = 0.37, p = 0.02) and patients with higher baseline miRNA levels had longer OS (12.47 vs. 9.00 months). Our findings suggest that these three miRNAs may be novel candidates as non-invasive predictive markers of therapy outcomes. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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15 pages, 5758 KiB

Open AccessArticle

Expression Profiling of Coding and Noncoding RNAs in the Endometrium of Patients with Endometriosis

by Mi Ran Choi, Hye Jin Chang, Jeong-Hyeon Heo, Sun Hyung Yum, Eunae Jo, Miran Kim and Sang-Rae Lee

Int. J. Mol. Sci. 2024, 25(19), 10581; https://doi.org/10.3390/ijms251910581 - 1 Oct 2024

Viewed by 694

Abstract

The aim of this study was to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in the endometrium of individuals with and without endometriosis (EMS) during the proliferative (P) and secretory (S) phases of the menstrual cycle. Tissues were obtained from 18 control (CT; P-phase [pCT], n = 8; S-phase [sCT], n = 13) and 23 EMS patients (P-phase [pEMS], n = 13; S-phase [sEMS], n = 12). DElncRNAs and DEmRNAs were analyzed using total RNA-sequencing. In P-phase, expression of NONHSAG019742.2 and NONHSAT120701.2 was significantly higher in EMS than control patients, that of while NONHSAG048398.2 and NONHSAG016560.2 was lower in EMS patients. In S-phase, expression of NONHSAT000959.2, NONHSAT203423.1, and NONHSAG053769.2 was significantly increased in EMS patients, while that of NONHSAG012105.2 and NONHSAG020839.2 was lower. In addition, the expression of HSD11B2, THBS1, GPX3, and SHISA6 was similar to that of neighboring lncRNAs in both P- and S-phases. In contrast, ELP3 and NR4A1, respectively, were up- or downregulated in pEMS tissues. In sEMS, expression of LAMB3 and HIF1A was increased, while expression of PAM was reduced. Our findings on lncRNAs and mRNAs encourage not only exploration of the potential clinical applications of lncRNAs and mRNAs as prognostic or diagnostic biomarkers for EMS but also to gain valuable insights into its pathogenesis. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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11 pages, 2377 KiB

Open AccessArticle

Bioinformatic Analysis from a Descriptive Profile of miRNAs in Chronic Migraine

by Alvaro Jovanny Tovar-Cuevas, Roberto Carlos Rosales Gómez, Beatriz Teresita Martín-Márquez, Nathan Alejandro Peña Dueñas, Flavio Sandoval-García, Milton Omar Guzmán Ornelas, Mariana Chávez Tostado, Diana Mercedes Hernández Corona and Fernanda-Isadora Corona Meraz

Int. J. Mol. Sci. 2024, 25(19), 10491; https://doi.org/10.3390/ijms251910491 - 29 Sep 2024

Viewed by 614

Abstract

Chronic migraines have been described chiefly only from a clinical perspective. However, searching for reliable molecular markers has allowed for the discovery of the expression of different genes mainly associated with inflammation, neuro-vascularization, and pain-related pathways. The interest in microRNAs (miRs) that can regulate the expression of these genes has gained significant relevance since multiple miRs could play a key role in regulating these events. In this study, miRs were searched in samples from patients with chronic migraine, and the inclusion criteria were carefully reviewed. Different bioinformatic tools, such as miRbase, targetscan, miRPath, tissue atlas, and miR2Disease, were used to analyze the samples. Our findings revealed that some of the miRs were expressed more (miR-197, miR-101, miR-92a, miR-375, and miR-146b) and less (miR-133a/b, miR-134, miR-195, and miR-340) than others. We concluded that, during chronic migraine, common pathways, such as inflammation, vascularization, neurodevelopment, nociceptive pain, and pharmacological resistance, were associated with this disease. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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14 pages, 1756 KiB

Open AccessArticle

Serum Levels of miR-122-5p and miR-125a-5p Predict Hepatotoxicity Occurrence in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation

by Damian Mikulski, Kacper Kościelny, Izabela Dróżdż, Grzegorz Mirocha, Mateusz Nowicki, Małgorzata Misiewicz, Ewelina Perdas, Piotr Strzałka, Agnieszka Wierzbowska and Wojciech Fendler

Int. J. Mol. Sci. 2024, 25(8), 4355; https://doi.org/10.3390/ijms25084355 - 15 Apr 2024

Cited by 1 | Viewed by 1262

Abstract

Hepatic complications are an acknowledged cause of mortality and morbidity among patients undergoing hematopoietic stem cell transplantation. In this study, we aimed to evaluate the potential role in the prediction of liver injury of five selected microRNAs (miRNAs)—miR-122-5p, miR-122-3p, miR-15b-5p, miR-99b-5p, and miR-125a-5p—in the setting of autologous hematopoietic stem cell transplantation (ASCT). A total of 66 patients were included in the study: 50 patients (75.8%) with multiple myeloma (MM) and 16 (24.2%) with lymphoma. Blood samples were collected after the administration of the conditioning regimen, on the day of transplant (day 0). The expression levels of selected miRNAs were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using the miRCURY LNA miRNA Custom PCR Panels (QIAGEN). In a multivariate logistic regression analysis adjusted for age, sex, and the administered conditioning regimen, two miRNAs, hsa-miR-122-5p (odds ratio, OR 2.10, 95% confidence interval, CI: 1.29–3.42, p = 0.0029) and hsa-miR-125a-5p (OR 0.27, 95% CI: 0.11–0.71, p = 0.0079), were independent for hepatic toxicity occurrence during the 14 days after transplant. Our model in 10-fold cross-validation preserved its diagnostic potential with a receiver operating characteristics area under the curve (ROC AUC) of 0.75, 95% CI: 0.63–0.88 and at optimal cut-off reached 72.0% sensitivity and 74.4% specificity. An elevated serum level of miR-122-5p and decreased level of miR-125a-5p on day 0 are independent risk factors for hepatotoxicity in ASCT recipients, showing promise in accurately predicting post-ASCT complications. Identifying patients susceptible to complications has the potential to reduce procedure costs and optimize the selection of inpatient or outpatient procedures. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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14 pages, 1529 KiB

Open AccessArticle

The Screening of microRNAs in Chronic Myeloid Leukemia: A Clinical Evaluation

by Denise Kusma Wosniaki, Anelis Maria Marin, Rafaela Noga Oliveira, Gabriela Marino Koerich, Eduardo Cilião Munhoz, João Samuel de Holanda Farias, Miriam Perlingeiro Beltrame, Dalila Luciola Zanette and Mateus Nóbrega Aoki

Int. J. Mol. Sci. 2024, 25(6), 3363; https://doi.org/10.3390/ijms25063363 - 16 Mar 2024

Viewed by 1373

Abstract

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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20 pages, 1927 KiB

Open AccessArticle

Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans

by Rekha S. Patel, Meredith Krause-Hauch, Kimbra Kenney, Shannon Miles, Risa Nakase-Richardson and Niketa A. Patel

Int. J. Mol. Sci. 2024, 25(3), 1473; https://doi.org/10.3390/ijms25031473 - 25 Jan 2024

Cited by 3 | Viewed by 1756

Abstract

More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress disorder or neurological dysfunction. This study sought to determine a long noncoding RNA (lncRNA) expression signature in serum samples that correlated with rmTBI years after the incidences. Serum samples were obtained from Long-Term Impact of Military-Relevant Brain-Injury Consortium Chronic Effects of Neurotrauma Consortium (LIMBIC CENC) repository, from participants unexposed to TBI or who had rmTBI. Four lncRNAs were identified as consistently present in all samples, as detected via droplet digital PCR and packaged in exosomes enriched for CNS origin. The results, using qPCR, demonstrated that the lncRNA VLDLR-AS1 levels were significantly lower among individuals with rmTBI compared to those with no lifetime TBI. ROC analysis determined an AUC of 0.74 (95% CI: 0.6124 to 0.8741; p = 0.0012). The optimal cutoff for VLDLR-AS1 was ≤153.8 ng. A secondary analysis of clinical data from LIMBIC CENC was conducted to evaluate the psychological symptom burden, and the results show that lncRNAs VLDLR-AS1 and MALAT1 are correlated with symptoms of depression. In conclusion, lncRNA VLDLR-AS1 may serve as a blood biomarker for identifying chronic rmTBI and depression in patients. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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17 pages, 2116 KiB

Open AccessArticle

Plasma Circular-RNA 0005567 as a Potential Marker of Disease Activity in Rheumatoid Arthritis

by Marek Cieśla, Dorota A. Darmochwal-Kolarz, Konrad Kwaśniak, Anna Pałka and Bogdan Kolarz

Int. J. Mol. Sci. 2024, 25(1), 417; https://doi.org/10.3390/ijms25010417 - 28 Dec 2023

Viewed by 1095

Abstract

Circular RNAs (circRNAs) are noncoding molecules and are generated through back splicing, during which the 5′ and 3′ ends are covalently joined. Consequently, the lack of free ends makes them stable and resistant to exonucleases, and they become more suitable biomarkers than other noncoding RNAs. The aim of the study was to find an association between selected circRNAs and disease activity in patients with RA. A total of 71 subjects, 45 patients with RA and 26 healthy controls (HCs), were enrolled. In the RA group, 24 patients had high disease activity (DAS-28-ESR > 5.1) and 21 individuals were in remission (DAS-28-ESR ≤ 2.6). The cell line SW982 was used to evaluate the biological function of circ_0005567. The concentration of circ_0005567 in RA patients was elevated compared to HCs (median, 177.5 [lower–upper quartile, 83.13–234.6] vs. 97.83 [42.03–145.4], p = 0.017). Patients with high disease activity had a higher concentration of circ_0005567 than the control group (185.4 [112.72–249.25] vs. 97.83 [42.03–145.4], p = 0.015). In the cell line model, we found an association between circ_0005567 and miR-194-5p concentration and increased expression of mRNAs that may be related to cell proliferation. The plasma concentration of circ_0005567 may be a new potential biomarker associated with disease activity in patients with RA. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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Review

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67 pages, 2808 KiB

Open AccessReview

Circulating Liquid Biopsy Biomarkers in Glioblastoma: Advances and Challenges

by Attila A. Seyhan

Int. J. Mol. Sci. 2024, 25(14), 7974; https://doi.org/10.3390/ijms25147974 - 21 Jul 2024

Cited by 2 | Viewed by 2910

Abstract

Gliomas, particularly glioblastoma (GBM), represent the most prevalent and aggressive tumors of the central nervous system (CNS). Despite recent treatment advancements, patient survival rates remain low. The diagnosis of GBM traditionally relies on neuroimaging methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scans and postoperative confirmation via histopathological and molecular analysis. Imaging techniques struggle to differentiate between tumor progression and treatment-related changes, leading to potential misinterpretation and treatment delays. Similarly, tissue biopsies, while informative, are invasive and not suitable for monitoring ongoing treatments. These challenges have led to the emergence of liquid biopsy, particularly through blood samples, as a promising alternative for GBM diagnosis and monitoring. Presently, blood and cerebrospinal fluid (CSF) sampling offers a minimally invasive means of obtaining tumor-related information to guide therapy. The idea that blood or any biofluid tests can be used to screen many cancer types has huge potential. Tumors release various components into the bloodstream or other biofluids, including cell-free nucleic acids such as microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs) or exosomes, metabolites, and other factors. These factors have been shown to cross the blood-brain barrier (BBB), presenting an opportunity for the minimally invasive monitoring of GBM as well as for the real-time assessment of distinct genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes associated with brain tumors. Despite their potential, the clinical utility of liquid biopsy-based circulating biomarkers is somewhat constrained by limitations such as the absence of standardized methodologies for blood or CSF collection, analyte extraction, analysis methods, and small cohort sizes. Additionally, tissue biopsies offer more precise insights into tumor morphology and the microenvironment. Therefore, the objective of a liquid biopsy should be to complement and enhance the diagnostic accuracy and monitoring of GBM patients by providing additional information alongside traditional tissue biopsies. Moreover, utilizing a combination of diverse biomarker types may enhance clinical effectiveness compared to solely relying on one biomarker category, potentially improving diagnostic sensitivity and specificity and addressing some of the existing limitations associated with liquid biomarkers for GBM. This review presents an overview of the latest research on circulating biomarkers found in GBM blood or CSF samples, discusses their potential as diagnostic, predictive, and prognostic indicators, and discusses associated challenges and future perspectives. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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30 pages, 1898 KiB

Open AccessReview

The Circulating Biomarkers League: Combining miRNAs with Cell-Free DNAs and Proteins

by Kyriacos Felekkis and Christos Papaneophytou

Int. J. Mol. Sci. 2024, 25(6), 3403; https://doi.org/10.3390/ijms25063403 - 17 Mar 2024

Cited by 6 | Viewed by 3104

Abstract

The potential of liquid biopsy for the prognosis and diagnosis of diseases is unquestionable. Within the evolving landscape of disease diagnostics and personalized medicine, circulating microRNAs (c-miRNAs) stand out among the biomarkers found in blood circulation and other biological fluids due to their stability, specificity, and non-invasive detection in biofluids. However, the complexity of human diseases and the limitations inherent in single-marker diagnostics highlight the need for a more integrative approach. It has been recently suggested that a multi-analyte approach offers advantages over the single-analyte approach in the prognosis and diagnosis of diseases. In this review, we explore the potential of combining three well-studied classes of biomarkers found in blood circulation and other biofluids—miRNAs, DNAs, and proteins—to enhance the accuracy and efficacy of disease detection and monitoring. Initially, we provide an overview of each biomarker class and discuss their main advantages and disadvantages highlighting the superiority of c-miRNAs over the other classes of biomarkers. Additionally, we discuss the challenges and future directions in integrating these biomarkers into clinical practice, emphasizing the need for standardized protocols and further validation studies. This integrated approach has the potential to revolutionize precision medicine by offering insights into disease mechanisms, facilitating early detection, and guiding personalized therapeutic strategies. The collaborative power of c-miRNAs with other biomarkers represents a promising frontier in the comprehensive understanding and management of complex diseases. Nevertheless, several challenges must be addressed before this approach can be translated into clinical practice. Full article

(This article belongs to the Special Issue Circulating Non-coding RNAs as Diagnostic and Prognostic Markers of Human Diseases: 2nd Edition)

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