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Roles of Non-coding RNAs in Diseases

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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: 31 July 2024 | Viewed by 6921

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Dr. Mariangela Morlando

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Department of Pharmaceutical Sciences, University of Perugia, Via del Giochetto, 06123 Perugia, Italy
Interests: molecular biology; regulation of gene expression; noncoding RNA biogenesis and function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-coding RNA (ncRNA) molecules, including small, long and circular ncRNAs, are a diverse class of RNA molecules that do not encode proteins but play important regulatory roles in cell homeostasis and organismal development. Small ncRNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs) and the emerging class of tRNA derived-tRNA fragments (tRFs), are generally involved in post-transcriptional gene regulation. Long and circular ncRNAs, on the other hand, are typically greater than 200 nucleotides in length and can regulate gene expression at both the transcriptional and post-transcriptional levels.

Besides physiological processes the roles of ncRNAs in the development and progression of various diseases have been extensively studied over the past few decades. For instance, ncRNAs have been shown to play important roles in cancer, cardiovascular diseases, neurodegenerative disorders, and metabolic disorders. Dysregulation of ncRNA expression or function can contribute to aberrant gene expression and signaling pathways, leading to disease pathology. Therefore, understanding the roles of ncRNAs in disease may provide new opportunities for developing diagnostic and therapeutic strategies.

This Special Issue is aimed at collecting latest advances and outstanding researches investigating the role of ncRNAs in the development and progression of various human diseases. Original Research papers and Reviews are welcome.

Dr. Mariangela Morlando
Guest Editor

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Published Papers (7 papers)

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Research

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13 pages, 2355 KiB

Open AccessArticle

LINC00662 Promotes Aggressive Traits by Modulating OCT4 Expression through miR-335-5p in Gallbladder Cancer Cells

by Pablo Pérez-Moreno, Ismael Riquelme, Carolina Bizama, Luis Vergara-Gómez, Julio C. Tapia, Priscilla Brebi, Patricia García and Juan Carlos Roa

Int. J. Mol. Sci. 2024, 25(12), 6740; https://doi.org/10.3390/ijms25126740 - 19 Jun 2024

Viewed by 641

Abstract

Long non-coding RNAs (lncRNAs) are nucleotide sequences that participate in different biological processes and are associated with different pathologies, including cancer. Long intergenic non-protein-coding RNA 662 (LINC00662) has been reported to be involved in different cancers, including colorectal, prostate, and breast cancer. However, its role in gallbladder cancer has not yet been described. In this article, we hypothesize that LINC00662 has an important role in the acquisition of aggressiveness traits such as a stem-like phenotype, invasion, and chemoresistance in gallbladder cancer. Here, we show that LINC00662 is associated with larger tumor size and lymph node metastasis in patients with gallbladder cancer. Furthermore, we show that the overexpression of LINC00662 promotes an increase in CD133⁺/CD44⁺ cell populations and the expression of stemness-associated genes. LINC00662 promotes greater invasive capacity and the expression of genes associated with epithelial–mesenchymal transition. In addition, the expression of LINC00662 promotes resistance to cisplatin and 5-fluorouracil, associated with increased expression of chemoresistance-related ATP-binding cassette (ABC) transporters in gallbladder cancer (GBC) cell lines. Finally, we show that the mechanism by which LINC00662 exerts its function is through a decrease in microRNA 335-5p (miR-335-5p) and an increase in octamer-binding transcription factor 4 (OCT4) in GBC cells. Thus, our data allow us to propose LINC00662 as a biomarker of poor prognosis and a potential therapeutic target for patients with GBC. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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17 pages, 10425 KiB

Open AccessArticle

MicroRNA-10 Family Promotes Renal Fibrosis through the VASH-1/Smad3 Pathway

by Yichen Shuai, Na Xu, Chuan Zhao, Fengrui Yang, Zhifen Ning and Guoxia Li

Int. J. Mol. Sci. 2024, 25(10), 5232; https://doi.org/10.3390/ijms25105232 - 11 May 2024

Viewed by 636

Abstract

Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-β1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-β1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3’UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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18 pages, 6909 KiB

Open AccessArticle

Transcriptomic Analyses and Experimental Validation Identified Immune-Related lncRNA–mRNA Pair MIR210HG–BPIFC Regulating the Progression of Hypertrophic Cardiomyopathy

by Yuan Zhang, Jiuxiao Zhao, Qiao Jin and Lenan Zhuang

Int. J. Mol. Sci. 2024, 25(5), 2816; https://doi.org/10.3390/ijms25052816 - 29 Feb 2024

Viewed by 1057

Abstract

Hypertrophic cardiomyopathy (HCM) is a disease in which the myocardium of the heart becomes asymmetrically thickened, malformed, disordered, and loses its normal structure and function. Recent studies have demonstrated the significant involvement of inflammatory responses in HCM. However, the precise role of immune-related long non-coding RNAs (lncRNAs) in the pathogenesis of HCM remains unclear. In this study, we performed a comprehensive analysis of immune-related lncRNAs in HCM. First, transcriptomic RNA-Seq data from both HCM patients and healthy individuals (GSE180313) were reanalyzed thoroughly. Key HCM-related modules were identified using weighted gene co-expression network analysis (WGCNA). A screening for immune-related lncRNAs was conducted within the key modules using immune-related mRNA co-expression analysis. Based on lncRNA–mRNA pairs that exhibit shared regulatory microRNAs (miRNAs), we constructed a competing endogenous RNA (ceRNA) network, comprising 9 lncRNAs and 17 mRNAs that were significantly correlated. Among the 26 lncRNA–mRNA pairs, only the MIR210HG–BPIFC pair was verified by another HCM dataset (GSE130036) and the isoprenaline (ISO)-induced HCM cell model. Furthermore, knockdown of MIR210HG increased the regulatory miRNAs and decreased the mRNA expression of BPIFC correspondingly in AC16 cells. Additionally, the analysis of immune cell infiltration indicated that the MIR210HG–BPIFC pair was potentially involved in the infiltration of naïve CD4⁺ T cells and CD8⁺ T cells. Together, our findings indicate that the decreased expression of the lncRNA–mRNA pair MIR210HG–BPIFC was significantly correlated with the pathogenesis of the disease and may be involved in the immune cell infiltration in the mechanism of HCM. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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15 pages, 3632 KiB

Open AccessArticle

miR-124 and VAMP3 Act Antagonistically in Human Neuroblastoma

by Xiaoxiao Zhang, Chengyong Yang, Zhen Meng, Huanhuan Zhong, Xutian Hou, Fenfen Wang, Yiping Lu, Jingjing Guo and Yan Zeng

Int. J. Mol. Sci. 2023, 24(19), 14877; https://doi.org/10.3390/ijms241914877 - 4 Oct 2023

Cited by 2 | Viewed by 1073

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor that affects developing nerve cells in the fetus, infants, and children. miR-124 is a microRNA (miRNA) enriched in neuronal tissues, and VAMP3 (vesicle-associated membrane protein 3) has been reported to be an miR-124 target, although the relationship between NB and miR-124 or VAMP3 is unknown. Our current work identified that miR-124 levels are high in NB cases and that elevated miR-124 correlates with worse NB outcomes. Conversely, depressed VAMP3 correlates with worse NB outcomes. To investigate the mechanisms by which miR-124 and VAMP3 regulate NB, we altered miR-124 or VAMP3 expression in human NB cells and observed that increased miR-124 and reduced VAMP3 stimulated cell proliferation and suppressed apoptosis, while increased VAMP3 had the opposite effects. Genome-wide mRNA expression analyses identified gene and pathway changes which might explain the NB cell phenotypes. Together, our studies suggest that miR-124 and VAMP3 could be potential new markers of NB and targets of NB treatments. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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22 pages, 8583 KiB

Open AccessArticle

Human lncRNA SUGCT-AS1 Regulates the Proinflammatory Response of Macrophage

by Yeong-Hwan Lim, Gwangho Yoon, Yeongseo Ryu, Dahee Jeong, Juhyun Song, Yong Sook Kim, Youngkeun Ahn, Hyun Kook and Young-Kook Kim

Int. J. Mol. Sci. 2023, 24(17), 13315; https://doi.org/10.3390/ijms241713315 - 28 Aug 2023

Cited by 2 | Viewed by 1311

Abstract

Macrophages are the major primary immune cells that mediate the inflammatory response. In this process, long non-coding RNAs (lncRNAs) play an important, yet largely unknown role. Therefore, utilizing several publicly available RNA sequencing datasets, we predicted and selected lncRNAs that are differentially expressed in M1 or M2 macrophages and involved in the inflammatory response. We identified SUGCT-AS1, which is a human macrophage-specific lncRNA whose expression is increased upon M1 macrophage stimulation. Conditioned media of SUGCT-AS1-depleted M1 macrophages induced an inflammatory phenotype of vascular smooth muscle cells, which included increased expression of inflammatory genes (IL1B and IL6), decreased contractile marker proteins (ACTA2 and SM22α), and increased cell migration. Depletion of SUGCT-AS1 promoted the expression and secretion of proinflammatory cytokines, such as TNF, IL1B, and IL6, in M1 macrophages, and transcriptomic analysis showed that SUGCT-AS1 has functions related to inflammatory responses and cytokines. Furthermore, we found that SUGCT-AS1 directly binds to hnRNPU and regulates its nuclear–cytoplasmic translocation. This translocation of hnRNPU altered the proportion of the MALT1 isoforms by regulating the alternative splicing of MALT1, a mediator of NF-κB signaling. Overall, our findings suggest that lncRNAs can be used for future studies on macrophage regulation. Moreover, they establish the SUGCT-AS1/hnRNPU/MALT1 axis, which is a novel inflammatory regulatory mechanism in macrophages. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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Review

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16 pages, 1892 KiB

Open AccessReview

Nuclear miRNAs: Gene Regulation Activities

by Monia Billi, Elisabetta De Marinis, Martina Gentile, Clara Nervi and Francesco Grignani

Int. J. Mol. Sci. 2024, 25(11), 6066; https://doi.org/10.3390/ijms25116066 - 31 May 2024

Viewed by 429

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs which contribute to the regulation of many physiological and pathological processes. Conventionally, miRNAs perform their activity in the cytoplasm where they regulate gene expression by interacting in a sequence-specific manner with mature messenger RNAs. Recent studies point to the presence of mature miRNAs in the nucleus. This review summarizes current findings regarding the molecular activities of nuclear miRNAs. These molecules can regulate gene expression at the transcriptional level by directly binding DNA on the promoter or the enhancer of regulated genes. miRNAs recruit different protein complexes to these regions, resulting in activation or repression of transcription, through a number of molecular mechanisms. Hematopoiesis is presented as a paradigmatic biological process whereby nuclear miRNAs possess a relevant regulatory role. Nuclear miRNAs can influence gene expression by affecting nuclear mRNA processing and by regulating pri-miRNA maturation, thus impacting the biogenesis of miRNAs themselves. Overall, nuclear miRNAs are biologically active molecules that can be critical for the fine tuning of gene expression and deserve further studies in a number of physiological and pathological conditions. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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21 pages, 1221 KiB

Open AccessReview

Deciphering the Enigmatic Influence: Non-Coding RNAs Orchestrating Wnt/β-Catenin Signaling Pathway in Tumor Progression

by Xinbing Yang, Yajing Du, Lulu Luo, Xinru Xu, Shizheng Xiong, Xueni Yang, Li Guo and Tingming Liang

Int. J. Mol. Sci. 2023, 24(18), 13909; https://doi.org/10.3390/ijms241813909 - 10 Sep 2023

Cited by 1 | Viewed by 1129

Abstract

Dysregulated expression of specific non-coding RNAs (ncRNAs) has been strongly linked to tumorigenesis, cancer progression, and therapeutic resistance. These ncRNAs can act as either oncogenes or tumor suppressors, thereby serving as valuable diagnostic and prognostic markers. Numerous studies have implicated the participation of ncRNAs in the regulation of diverse signaling pathways, including the pivotal Wnt/β-catenin signaling pathway that is widely acknowledged for its pivotal role in embryogenesis, cellular proliferation, and tumor biology control. Recent emerging evidence has shed light on the capacity of ncRNAs to interact with key components of the Wnt/β-catenin signaling pathway, thereby modulating the expression of Wnt target genes in cancer cells. Notably, the activity of this pathway can reciprocally influence the expression levels of ncRNAs. However, comprehensive analysis investigating the specific ncRNAs associated with the Wnt/β-catenin signaling pathway and their intricate interactions in cancer remains elusive. Based on these noteworthy findings, this review aims to unravel the intricate associations between ncRNAs and the Wnt/β-catenin signaling pathway during cancer initiation, progression, and their potential implications for therapeutic interventions. Additionally, we provide a comprehensive overview of the characteristics of ncRNAs and the Wnt/β-catenin signaling pathway, accompanied by a thorough discussion of their functional roles in tumor biology. Targeting ncRNAs and molecules associated with the Wnt/β-catenin signaling pathway may emerge as a promising and effective therapeutic strategy in future cancer treatments. Full article

(This article belongs to the Special Issue Roles of Non-coding RNAs in Diseases)

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