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RNA Regulatory Networks at the Crossroad of Human Diseases 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 21136

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Prof. Nicoletta Potenza

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Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania “L. Vanvitelli”, Via Vivaldi, 43-81100 Caserta, Italy
Interests: microRNAs; lncRNA; non-coding RNA; cancer
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Special Issue Information

Dear Colleagues,

This Special Issue is the third volume of "RNA Regulatory Networks at the Crossroad of Human Diseases" and "RNA Regulatory Networks at the Crossroad of Human Diseases 2.0". Exploration of the transcriptome space has turned the spotlight on the dark side of the RNA planet, noncoding RNAs (ncRNAs), which have been previously overlooked by conventional protein-coding studies. It has become increasingly clear that ncRNAs constitute the largest class of RNA transcripts, resulting from pervasive transcription of the genome, of which only 1–2% code for proteins. ncRNAs comprise different RNA species, which can be broadly categorized into short ncRNAs, including microRNAs (miRNA), and long ncRNAs (lncRNAs), such as lincRNAs, antisense RNAs, pseudogenes and circular RNAs. We are in an exciting era, with the unveiling of the previously unappreciated regulatory power of all these RNA species and their functional interactions. Various studies have demonstrated that ncRNAs engage in competitive regulatory interactions, known as competing endogenous RNA (ceRNA) networks, ceRNETs, whereby miRNAs and lncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs by competing in binding to mRNA targets. In this scenario, coding transcripts themselves could have a regulatory potential beyond their coding power when they compete for binding to shared miRNAs.

Research on such RNA-based networks is now outlining their relevant role in a wide range of biological pathways; the unbalancing of any network component can act as a driving force for human diseases, as demonstrated for various cancer types. While ceRNET research is still in its infancy, further advancements could help us gain deeper insights into molecular mechanisms underlying human diseases and even the identification of new biomarkers and therapeutic targets.

This Special Issue welcomes original research manuscripts unraveling novel RNA regulatory networks, their impact on human diseases and possible rules for ncRNA structure-function relationships; those reporting innovative methodological approaches, including new bioinformatics tools; and critical review manuscripts outlining various perspectives to set the stage for future research.

Prof. Nicoletta Potenza
Guest Editor

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Keywords

noncoding RNA
microRNA
piRNA
lncRNA
circRNA
disease pathogenesis
developmental defects
cancer

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Published Papers (9 papers)

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Research

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15 pages, 2158 KiB

Open AccessArticle

The Role of hsa-miR-125b-5p Interaction with S1P/Ceramide Axis in the Potential Development of Inflammation-Associated Colon Cancer in Primary Sclerosing Cholangitis

by Joanna Abramczyk, Malgorzata Milkiewicz, Bartosz Hula, Piotr Milkiewicz and Agnieszka Kempinska-Podhorodecka

Int. J. Mol. Sci. 2023, 24(11), 9175; https://doi.org/10.3390/ijms24119175 - 24 May 2023

Cited by 3 | Viewed by 2058

Abstract

Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis that can lead to MSI-H cancer progression in PSC/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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18 pages, 4149 KiB

Open AccessArticle

Inter- and Intramolecular RNA–RNA Interactions Modulate the Regulation of Translation Mediated by the 3′ UTR in West Nile Virus

by Cristina Romero-López, Margarita Roda-Herreros, Beatriz Berzal-Herranz, Sara Esther Ramos-Lorente and Alfredo Berzal-Herranz

Int. J. Mol. Sci. 2023, 24(6), 5337; https://doi.org/10.3390/ijms24065337 - 10 Mar 2023

Cited by 3 | Viewed by 1900

Abstract

RNA viruses rely on genomic structural elements to accomplish the functions necessary to complete the viral cycle. These elements participate in a dynamic network of RNA–RNA interactions that determine the overall folding of the RNA genome and may be responsible for the fine regulation of viral replication and translation as well as the transition between them. The genomes of members of the genus Flavivirus are characterized by a complexly folded 3′ UTR with a number of RNA structural elements that are conserved across isolates of each species. The present work provides evidence of intra- and intermolecular RNA–RNA interactions involving RNA structural elements in the 3′ UTR of the West Nile virus genome. The intermolecular interactions can be visualized in vitro by the formation of molecular dimers involving the participation of at least the SLI and 3′DB elements. Certainly, the 3′ UTR of dengue virus, which lacks the SLI element, forms molecular dimers in lower quantities via a single interaction site, probably 3′DB. The functional analysis of sequence or deletion mutants revealed an inverse relationship between 3′ UTR dimerization and viral translation efficiency in cell cultures. A network of RNA–RNA interactions involving 3′ UTR structural elements might therefore exist, helping to regulate viral translation. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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16 pages, 3289 KiB

Open AccessArticle

LncRNA CASC19 Enhances the Radioresistance of Nasopharyngeal Carcinoma by Regulating the miR-340-3p/FKBP5 Axis

by Hongxia Liu, Qianping Chen, Wang Zheng, Yuchuan Zhou, Yang Bai, Yan Pan, Jianghong Zhang and Chunlin Shao

Int. J. Mol. Sci. 2023, 24(3), 3047; https://doi.org/10.3390/ijms24033047 - 3 Feb 2023

Cited by 8 | Viewed by 3043

Abstract

Radioresistance remains a serious obstacle encountered in the radiotherapy of nasopharyngeal carcinoma (NPC). Both mRNAs and non-coding RNAs (ncRNAs), including long ncRNA (lncRNA) and microRNA (miRNA), play essential roles in radiosensitivity. However, the comprehensive expression profiles and competing endogenous RNA (ceRNA) regulatory networks among lncRNAs, miRNAs, and mRNAs in NPC radioresistance are still bewildering. In this study, we performed an RNA-sequencing (RNA-seq) assay in the radioresistant NPC cells CNE2R and its parental cells CNE2 to identify the differentially expressed lncRNAs, miRNAs, and mRNAs. The ceRNA networks containing lncRNAs, miRNAs, and mRNAs were predicted on the basis of the Pearson correlation coefficients and authoritative miRanda databases. In accordance with bioinformatic analysis of the data of the tandem mass tag (TMT) assay of CNE2R and CNE2 cells and the gene chip assay of radioresistant NPC samples in pre- and post-radiotherapy, the radioresistance-related signaling network of lncRNA CASC19, miR-340-3p, and FKBP5 was screened and further verified using an RT-qPCR assay. CASC19 was positively associated with FKBP5 expression while negatively correlated with miR-340-3p, and the target binding sites of CASC19/miR-340-3p and miR-340-3p/FKBP5 were confirmed using a dual-luciferase reporter assay. Moreover, using an mRFP–GFP–LC3 maker, it was found that autophagy contributed to the radioresistance of NPC. MiR-340-3p inhibition or FKBP5 overexpression could rescue the suppression of autophagy and radioresistance induced by CASC19 knockdown in CNE2R cells. In conclusion, the CASC19/miR-340-3p/FKBP5 network may be instrumental in regulating NPC radioresistance by enhancing autophagy, which provides potential new therapeutic targets for NPC. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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19 pages, 6504 KiB

Open AccessArticle

The RNA-Binding Protein SMN as a Novel Player in Laryngeal Squamous Cell Carcinoma

by Francesca Gabanella, Andrea Colizza, Maria Chiara Mottola, Silvia Francati, Giovanna Blaconà, Carla Petrella, Christian Barbato, Antonio Greco, Massimo Ralli, Marco Fiore, Nicoletta Corbi, Giampiero Ferraguti, Alessandro Corsi, Antonio Minni, Marco de Vincentiis, Claudio Passananti and Maria Grazia Di Certo

Int. J. Mol. Sci. 2023, 24(2), 1794; https://doi.org/10.3390/ijms24021794 - 16 Jan 2023

Cited by 5 | Viewed by 2216

Abstract

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium in the oral cavity, pharynx, sino-nasal region, and larynx. Laryngeal squamous cell carcinoma (LSCC) represents one-third of all head and neck cancers. Dysregulated RNA-related pathways define an important molecular signature in this aggressive carcinoma. The Survival Motor Neuron (SMN) protein regulates fundamental aspects of the RNA metabolism but, curiously, its role in cancer is virtually unknown. For the first time, here, we focus on the SMN in the cancer context. We conducted a pilot study in a total of 20 patients with LSCC where the SMN was found overexpressed at both the protein and transcript levels. By a cellular model of human laryngeal carcinoma, we demonstrated that the SMN impacts cancer-relevant behaviors and perturbs key players of cell migration, invasion, and adhesion. Furthermore, in LSCC we showed a physical interaction between the SMN and the epidermal growth factor receptor (EGFR), whose overexpression is an important feature in these tumors. This study proposes the SMN protein as a novel therapeutic target in LSSC and likely in the whole spectrum of HNSCC. Overall, we provide the first analysis of the SMN in human cancer. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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Review

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15 pages, 1218 KiB

Open AccessReview

Early Splicing Complexes and Human Disease

by Chloe K. Nagasawa and Mariano A. Garcia-Blanco

Int. J. Mol. Sci. 2023, 24(14), 11412; https://doi.org/10.3390/ijms241411412 - 13 Jul 2023

Cited by 3 | Viewed by 2602

Abstract

Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on human disease. As a result, targeted splicing therapeutics have been developed, treating various diseases including spinal muscular atrophy and Duchenne muscular dystrophy. These advancements are very promising and emphasize the critical role of proper splicing in maintaining human health. Herein, we provide an overview of the current information on the composition and assembly of early splicing complexes—commitment complex and pre-spliceosome—and their association with human disease. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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19 pages, 2685 KiB

Open AccessReview

Interactome of Long Non-Coding RNAs: Transcriptomic Expression Patterns and Shaping Cancer Cell Phenotypes

by Nicole R. DeSouza, Danielle Quaranto, Michelle Carnazza, Tara Jarboe, Raj K. Tiwari and Jan Geliebter

Int. J. Mol. Sci. 2023, 24(12), 9914; https://doi.org/10.3390/ijms24129914 - 8 Jun 2023

Cited by 4 | Viewed by 1850

Abstract

RNA biology has gained extensive recognition in the last two decades due to the identification of novel transcriptomic elements and molecular functions. Cancer arises, in part, due to the accumulation of mutations that greatly contribute to genomic instability. However, the identification of differential gene expression patterns of wild-type loci has exceeded the boundaries of mutational study and has significantly contributed to the identification of molecular mechanisms that drive carcinogenic transformation. Non-coding RNA molecules have provided a novel avenue of exploration, providing additional routes for evaluating genomic and epigenomic regulation. Of particular focus, long non-coding RNA molecule expression has been demonstrated to govern and direct cellular activity, thus evidencing a correlation between aberrant long non-coding RNA expression and the pathological transformation of cells. lncRNA classification, structure, function, and therapeutic utilization have expanded cancer studies and molecular targeting, and understanding the lncRNA interactome aids in defining the unique transcriptomic signatures of cancer cell phenotypes. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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26 pages, 1408 KiB

Open AccessReview

Making Sense of Antisense lncRNAs in Hepatocellular Carcinoma

by Nicola Mosca, Aniello Russo and Nicoletta Potenza

Int. J. Mol. Sci. 2023, 24(10), 8886; https://doi.org/10.3390/ijms24108886 - 17 May 2023

Cited by 6 | Viewed by 2047

Abstract

Transcriptome complexity is emerging as an unprecedented and fascinating domain, especially by high-throughput sequencing technologies that have unveiled a plethora of new non-coding RNA biotypes. This review covers antisense long non-coding RNAs, i.e., lncRNAs transcribed from the opposite strand of other known genes, and their role in hepatocellular carcinoma (HCC). Several sense–antisense transcript pairs have been recently annotated, especially from mammalian genomes, and an understanding of their evolutionary sense and functional role for human health and diseases is only beginning. Antisense lncRNAs dysregulation is significantly involved in hepatocarcinogenesis, where they can act as oncogenes or oncosuppressors, thus playing a key role in tumor onset, progression, and chemoradiotherapy response, as deduced from many studies discussed here. Mechanistically, antisense lncRNAs regulate gene expression by exploiting various molecular mechanisms shared with other ncRNA molecules, and exploit special mechanisms on their corresponding sense gene due to sequence complementarity, thus exerting epigenetic, transcriptional, post-transcriptional, and translational controls. The next challenges will be piecing together the complex RNA regulatory networks driven by antisense lncRNAs and, ultimately, assigning them a function in physiological and pathological contexts, in addition to defining prospective novel therapeutic targets and innovative diagnostic tools. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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35 pages, 1862 KiB

Open AccessReview

Mutual Regulation of ncRNAs and Chromatin Remodeling Complexes in Normal and Pathological Conditions

by Irina V. Bure and Marina V. Nemtsova

Int. J. Mol. Sci. 2023, 24(9), 7848; https://doi.org/10.3390/ijms24097848 - 25 Apr 2023

Cited by 7 | Viewed by 2154

Abstract

Chromatin remodeling is the one of the main epigenetic mechanisms of gene expression regulation both in normal cells and in pathological conditions. In recent years, a growing number of investigations have confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. Genes encoding protein subunits of chromatin remodeling complexes are often mutated and change their expression in diseases, as well as non-coding RNAs (ncRNAs). Moreover, different mechanisms of their mutual regulation have already been described. Further understanding of these processes may help apply their clinical potential for establishment of the diagnosis, prognosis, and treatment of the diseases. The therapeutic targeting of the chromatin structure has many limitations because of the complexity of its regulation, with the involvement of a large number of genes, proteins, non-coding transcripts, and other intermediary molecules. However, several successful strategies have been proposed to target subunits of chromatin remodeling complexes and genes encoding them, as well as the ncRNAs that regulate the operation of these complexes and direct them to the target gene regions. In our review, we focus on chromatin remodeling complexes and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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18 pages, 5993 KiB

Open AccessReview

MicroRNAs as Biomarkers of Surgical Outcome in Mesial Temporal Lobe Epilepsy: A Systematic Review

by Alexey M. Yakimov, Elena E. Timechko, Irina G. Areshkina, Anna A. Usoltseva, Kristina D. Yakovleva, Elena A. Kantimirova, Nikita Utyashev, Nikita Ivin and Diana V. Dmitrenko

Int. J. Mol. Sci. 2023, 24(6), 5694; https://doi.org/10.3390/ijms24065694 - 16 Mar 2023

Cited by 5 | Viewed by 2260

Abstract

Mesial temporal lobe epilepsy is the most common type of epilepsy. For most patients suffering from TLE, the only treatment option is surgery. However, there is a high possibility of relapse. Invasive EEG as a method for predicting the outcome of surgical treatment is a very complex and invasive manipulation, so the search for outcome biomarkers is an urgent task. MicroRNAs as potential biomarkers of surgical outcome are the subject of this study. For this study, a systematic search for publications in databases such as PubMed, Springer, Web of Science, Scopus, ScienceDirect, and MDPI was carried out. The following keywords were used: temporal lobe epilepsy, microRNA, biomarkers, surgery, and outcome. Three microRNAs were studied as prognostic biomarkers of surgical outcome: miR-27a-3p, miR-328-3p, and miR-654-3p. According to the results of the study, only miR-654-3p showed a good ability to discriminate between patients with poor and good surgical outcomes. MiR-654-3p is involved in the following biological pathways: ATP-binding cassette drug transporters, glutamate transporter SLC7A11, and TP53. A specific target for miR-654-3p is GLRA2, the glycine receptor subunit. MicroRNAs, which are diagnostic biomarkers of TLE, and epileptogenesis, miR-134-5p, MiR-30a, miRs-143, etc., can be considered as potential biomarkers of surgical outcome, as they can be indicators of early and late relapses. These microRNAs are involved in the processes characteristic of epilepsy: oxidative stress and apoptosis. The study of miRNAs as potential predictive biomarkers of surgical outcome is an urgent task and should be continued. However, when studying miRNA expression profiles, it is important to take into account and note a number of factors, such as the type of sample under study, the time of sampling for the study, the type and duration of the disease, and the type of antiepileptic treatment. Without taking into account all these factors, it is impossible to assess the influence and involvement of miRNAs in epileptic processes. Full article

(This article belongs to the Special Issue RNA Regulatory Networks at the Crossroad of Human Diseases 3.0)

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