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Non-Coding RNA, Volume 9, Issue 3 (June 2023) – 6 articles

Cover Story (view full-size image): The cellular roles of circular RNAs (circRNAs) are widely studied; albeit little is known about the effects of drugs on their expression and relationship with the cognate linear transcript (linRNA). Focusing on breast cancer, we tested various anticancer agents in two cell lines that comprise a panel of drug-modulated circRNAs/linRNAs. According to their oncogenic or anticancer role, we observed the upregulation of circRNA and downregulation of linRNA within the same gene in association with specific mutated pathways, such as PI3K/AKT in MCF-7 or the NHEJ DNA repair pathway in the TP53-mutated MDA-MB-231 cell. Interestingly, only XL765 did not alter tumorigenic circ/linRNAs in MCF-7, and AMG511 and GSK1070916 decreased circGFRA1, as drug effectiveness in MDA-MB-231 cells. View this paper

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7 pages, 806 KiB

Open AccessCommentary

Small Nucleolar (Sno)RNA: Therapy Lays in Translation

by Ofri Rabany and Daphna Nachmani

Non-Coding RNA 2023, 9(3), 35; https://doi.org/10.3390/ncrna9030035 - 8 Jun 2023

Cited by 3 | Viewed by 2267

Abstract

The ribosome is one of the largest complexes in the cell. Adding to its complexity are more than 200 RNA modification sites present on ribosomal RNAs (rRNAs) in a single human ribosome. These modifications occur in functionally important regions of the rRNA molecule, and they are vital for ribosome function and proper gene expression. Until recent technological advancements, the study of rRNA modifications and their profiles has been extremely laborious, leaving many questions unanswered. Small nucleolar RNAs (snoRNAs) are non-coding RNAs that facilitate and dictate the specificity of rRNA modification deposition, making them an attractive target for ribosome modulation. Here, we propose that through the mapping of rRNA modification profiles, we can identify cell-specific modifications with high therapeutic potential. We also describe the challenges of achieving the targeting specificity needed to implement snoRNAs as therapeutic targets in cancers. Full article

(This article belongs to the Special Issue Recent Advances in Chemical Biology to Study and Target ncRNAs)

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20 pages, 1349 KiB

Open AccessFeature PaperReview

A Review of IsomiRs in Colorectal Cancer

by Molly A. Lausten and Bruce M. Boman

Non-Coding RNA 2023, 9(3), 34; https://doi.org/10.3390/ncrna9030034 - 7 Jun 2023

Cited by 3 | Viewed by 2525

Abstract

As advancements in sequencing technology rapidly continue to develop, a new classification of microRNAs has occurred with the discovery of isomiRs, which are relatively common microRNAs with sequence variations compared to their established template microRNAs. This review article seeks to compile all known information about isomiRs in colorectal cancer (CRC), which has not, to our knowledge, been gathered previously to any great extent. A brief overview is given of the history of microRNAs, their implications in colon cancer, the canonical pathway of biogenesis and isomiR classification. This is followed by a comprehensive review of the literature that is available on microRNA isoforms in CRC. The information on isomiRs presented herein shows that isomiRs hold great promise for translation into new diagnostics and therapeutics in clinical medicine. Full article

(This article belongs to the Special Issue Small RNAs – Big Roles: IsomiRs, tRNA Fragments, and rRNA Fragments in Human Health and Disease)

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10 pages, 1110 KiB

Open AccessCommunication

A microRNA Arising from the Negative Strand of SARS-CoV-2 Genome Targets FOS to Reduce AP-1 Activity

by Francesco Greco, Elisa Lorefice, Claudia Carissimi, Ilaria Laudadio, Fabiola Ciccosanti, Martina Di Rienzo, Francesca Colavita, Silvia Meschi, Fabrizio Maggi, Gian Maria Fimia and Valerio Fulci

Non-Coding RNA 2023, 9(3), 33; https://doi.org/10.3390/ncrna9030033 - 23 May 2023

Cited by 2 | Viewed by 2350

Abstract

Virus-encoded microRNAs were first reported in the Epstein–Barr virus in 2004. Subsequently, a few hundred viral miRNAs have been identified, mainly in DNA viruses belonging to the herpesviridae family. To date, only 30 viral miRNAs encoded by RNA viruses are reported by miRBase. Since the outbreak of the SARS-CoV-2 pandemic, several studies have predicted and, in some cases, experimentally validated miRNAs originating from the positive strand of the SARS-CoV-2 genome. By integrating NGS data analysis and qRT-PCR approaches, we found that SARS-CoV-2 also encodes for a viral miRNA arising from the minus (antisense) strand of the viral genome, in the region encoding for ORF1ab, herein referred to as SARS-CoV-2-miR-AS1. Our data show that the expression of this microRNA increases in a time course analysis of SARS-CoV-2 infected cells. Furthermore, enoxacin treatment enhances the accumulation of the mature SARS-CoV-2-miR-AS1 in SARS-CoV-2 infected cells, arguing for a Dicer-dependent processing of this small RNA. In silico analysis suggests that SARS-CoV-2-miR-AS1 targets a set of genes which are translationally repressed during SARS-CoV-2 infection. We experimentally validated that SARS-CoV-2-miR-AS1 targets FOS, thus repressing the AP-1 transcription factor activity in human cells. Full article

(This article belongs to the Collection Non-Coding RNAs, COVID-19, and Long-COVID)

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16 pages, 4048 KiB

Open AccessArticle

Inverse Impact of Cancer Drugs on Circular and Linear RNAs in Breast Cancer Cell Lines

by Anna Terrazzan, Francesca Crudele, Fabio Corrà, Pietro Ancona, Jeffrey Palatini, Nicoletta Bianchi and Stefano Volinia

Non-Coding RNA 2023, 9(3), 32; https://doi.org/10.3390/ncrna9030032 - 19 May 2023

Viewed by 2619

Abstract

Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly, VRK1 and MAN1A2 were increased by several drugs in both cell lines. However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells. Full article

(This article belongs to the Special Issue ncRNAs to Target Molecular Pathways)

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13 pages, 2986 KiB

Open AccessArticle

Genetic Deletion of the LINC00520 Homolog in Mouse Aggravates Angiotensin II-Induced Hypertension

by Xiaofang Tang, Chih-Hung Lai, Naseeb K. Malhi, Rahuljeet Chadha, Yingjun Luo, Xuejing Liu, Dongqiang Yuan, Alonso Tapia, Maryam Abdollahi, Guangyu Zhang, Riccardo Calandrelli, Yan-Ting Shiu, Zhao V. Wang, June-Wha Rhee, Sheng Zhong, Rama Natarajan and Zhen Bouman Chen

Non-Coding RNA 2023, 9(3), 31; https://doi.org/10.3390/ncrna9030031 - 15 May 2023

Cited by 1 | Viewed by 2953

Abstract

(1) Background: Hypertension is a complex, multifactorial disease that is caused by genetic and environmental factors. Apart from genetic predisposition, the mechanisms involved in this disease have yet to be fully understood. We previously reported that LEENE (lncRNA enhancing endothelial nitric oxide expression, transcribed from LINC00520 in the human genome) regulates endothelial cell (EC) function by promoting the expression of endothelial nitric oxide synthase (eNOS) and vascular growth factor receptor 2 (VEGFR2). Mice with genetic deletion of the LEENE/LINC00520 homologous region exhibited impaired angiogenesis and tissue regeneration in a diabetic hindlimb ischemia model. However, the role of LEENE in blood pressure regulation is unknown. (2) Methods: We subjected mice with genetic ablation of leene and wild-type littermates to Angiotensin II (AngII) and monitored their blood pressure and examined their hearts and kidneys. We used RNA-sequencing to identify potential leene-regulated molecular pathways in ECs that contributed to the observed phenotype. We further performed in vitro experiments with murine and human ECs and ex vivo experiments with murine aortic rings to validate the select mechanism. (3) Results: We identified an exacerbated hypertensive phenotype of leene-KO mice in the AngII model, evidenced by higher systolic and diastolic blood pressure. At the organ level, we observed aggravated hypertrophy and fibrosis in the heart and kidney. Moreover, the overexpression of human LEENE RNA, in part, restored the signaling pathways impaired by leene deletion in murine ECs. Additionally, Axitinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR suppresses LEENE in human ECs. (4) Conclusions: Our study suggests LEENE as a potential regulator in blood pressure control, possibly through its function in ECs. Full article

(This article belongs to the Special Issue Women’s Special Issue Series: Noncoding RNAs and Diseases)

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20 pages, 2819 KiB

Open AccessFeature PaperArticle

T2DB: A Web Database for Long Non-Coding RNA Genes in Type II Diabetes

by Rebecca Distefano, Mirolyuba Ilieva, Jens Hedelund Madsen, Hideshi Ishii, Masanori Aikawa, Sarah Rennie and Shizuka Uchida

Non-Coding RNA 2023, 9(3), 30; https://doi.org/10.3390/ncrna9030030 - 8 May 2023

Cited by 5 | Viewed by 3594

Abstract

Type II diabetes (T2D) is a growing health problem worldwide due to increased levels of obesity and can lead to other life-threatening diseases, such as cardiovascular and kidney diseases. As the number of individuals diagnosed with T2D rises, there is an urgent need to understand the pathogenesis of the disease in order to prevent further harm to the body caused by elevated blood glucose levels. Recent advances in long non-coding RNA (lncRNA) research may provide insights into the pathogenesis of T2D. Although lncRNAs can be readily detected in RNA sequencing (RNA-seq) data, most published datasets of T2D patients compared to healthy donors focus only on protein-coding genes, leaving lncRNAs to be undiscovered and understudied. To address this knowledge gap, we performed a secondary analysis of published RNA-seq data of T2D patients and of patients with related health complications to systematically analyze the expression changes of lncRNA genes in relation to the protein-coding genes. Since immune cells play important roles in T2D, we conducted loss-of-function experiments to provide functional data on the T2D-related lncRNA USP30-AS1, using an in vitro model of pro-inflammatory macrophage activation. To facilitate lncRNA research in T2D, we developed a web application, T2DB, to provide a one-stop-shop for expression profiling of protein-coding and lncRNA genes in T2D patients compared to healthy donors or subjects without T2D. Full article

(This article belongs to the Special Issue Non-coding RNA and Diabetes 2.0)

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