Research

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

Viewed by 2361

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, [...] Read more.

(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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11 pages, 2279 KiB

Open AccessCommunication

Long Non-Coding RNA Expression in Alpha-1 Antitrypsin Deficient Monocytes Pre- and Post-AAT Augmentation Therapy

by Stephen G. J. Smith and Catherine M. Greene

Non-Coding RNA 2023, 9(1), 6; https://doi.org/10.3390/ncrna9010006 - 10 Jan 2023

Cited by 2 | Viewed by 1442

Abstract

Long non-coding RNAs (lncRNAs) regulate gene expression. Their expression in alpha-1 antitrypsin (AAT) deficiency has not been investigated. Treatment of AAT deficiency involves infusion of plasma-purified AAT and this augmentation therapy has previously been shown to alter microRNA expression in monocytes of AAT-deficient [...] Read more.

Long non-coding RNAs (lncRNAs) regulate gene expression. Their expression in alpha-1 antitrypsin (AAT) deficiency has not been investigated. Treatment of AAT deficiency involves infusion of plasma-purified AAT and this augmentation therapy has previously been shown to alter microRNA expression in monocytes of AAT-deficient (ZZ) individuals. Here, we assess the effect of AAT augmentation therapy on the lncRNA expression profile in ZZ monocytes. Peripheral blood monocytes were isolated from ZZ individuals pre (Day 0)- and post (Day 2)-AAT augmentation therapy. Arraystar lncRNA microarray profiling was performed; a total of 17,761 lncRNAs were detectable across all samples. The array identified 7509 lncRNAs with differential expression post-augmentation therapy, 3084 were increased and 4425 were decreased (fold change ≥ 2). Expression of many of these lncRNAs were similarly altered in ZZ monocytes treated ex vivo with 27.5 μM AAT for 4 h. These properties may contribute to the manifold effects of AAT augmentation therapy. Full article

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

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18 pages, 4308 KiB

Open AccessArticle

Flnc: Machine Learning Improves the Identification of Novel Long Noncoding RNAs from Stand-Alone RNA-Seq Data

by Zixiu Li, Peng Zhou, Euijin Kwon, Katherine A. Fitzgerald, Zhiping Weng and Chan Zhou

Non-Coding RNA 2022, 8(5), 70; https://doi.org/10.3390/ncrna8050070 - 13 Oct 2022

Cited by 2 | Viewed by 2473

Abstract

Long noncoding RNAs (lncRNAs) play critical regulatory roles in human development and disease. Although there are over 100,000 samples with available RNA sequencing (RNA-seq) data, many lncRNAs have yet to be annotated. The conventional approach to identifying novel lncRNAs from RNA-seq data is [...] Read more.

Long noncoding RNAs (lncRNAs) play critical regulatory roles in human development and disease. Although there are over 100,000 samples with available RNA sequencing (RNA-seq) data, many lncRNAs have yet to be annotated. The conventional approach to identifying novel lncRNAs from RNA-seq data is to find transcripts without coding potential but this approach has a false discovery rate of 30–75%. Other existing methods either identify only multi-exon lncRNAs, missing single-exon lncRNAs, or require transcriptional initiation profiling data (such as H3K4me3 ChIP-seq data), which is unavailable for many samples with RNA-seq data. Because of these limitations, current methods cannot accurately identify novel lncRNAs from existing RNA-seq data. To address this problem, we have developed software, Flnc, to accurately identify both novel and annotated full-length lncRNAs, including single-exon lncRNAs, directly from RNA-seq data without requiring transcriptional initiation profiles. Flnc integrates machine learning models built by incorporating four types of features: transcript length, promoter signature, multiple exons, and genomic location. Flnc achieves state-of-the-art prediction power with an AUROC score over 0.92. Flnc significantly improves the prediction accuracy from less than 50% using the conventional approach to over 85%. Flnc is available via GitHub platform. Full article

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

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14 pages, 3516 KiB

Open AccessArticle

Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

by Izabela Mamede C. A. da Conceição, Thomaz Luscher-Dias, Lúcio R. Queiroz, Ana Gabrielle B. de Melo, Carlos Renato Machado, Karina B. Gomes, Renan P. Souza, Marcelo R. Luizon and Glória R. Franco

Non-Coding RNA 2022, 8(5), 68; https://doi.org/10.3390/ncrna8050068 - 12 Oct 2022

Cited by 4 | Viewed by 2497

Abstract

Long noncoding RNAs (lncRNAs) undergo splicing and have multiple transcribed isoforms. Nevertheless, for lncRNAs, as well as for mRNA, measurements of expression are routinely performed only at the gene level. Metformin is the first-line oral therapy for type 2 diabetes mellitus and other [...] Read more.

Long noncoding RNAs (lncRNAs) undergo splicing and have multiple transcribed isoforms. Nevertheless, for lncRNAs, as well as for mRNA, measurements of expression are routinely performed only at the gene level. Metformin is the first-line oral therapy for type 2 diabetes mellitus and other metabolic diseases. However, its mechanism of action remains not thoroughly explained. Transcriptomic analyses using metformin in different cell types reveal that only protein-coding genes are considered. We aimed to characterize lncRNA isoforms that were differentially affected by metformin treatment on multiple human cell types (three cancer, two non-cancer) and to provide insights into the lncRNA regulation by this drug. We selected six series to perform a differential expression (DE) isoform analysis. We also inferred the biological roles for lncRNA DE isoforms using in silico tools. We found the same isoform of an lncRNA (AC016831.6-205) highly expressed in all six metformin series, which has a second exon putatively coding for a peptide with relevance to the drug action. Moreover, the other two lncRNA isoforms (ZBED5-AS1-207 and AC125807.2-201) may also behave as cis-regulatory elements to the expression of transcripts in their vicinity. Our results strongly reinforce the importance of considering DE isoforms of lncRNA for understanding metformin mechanisms at the molecular level. Full article

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

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9 pages, 1860 KiB

Open AccessArticle

Knockdown of lncRNA TP53TG1 Enhances the Efficacy of Sorafenib in Human Hepatocellular Carcinoma Cells

by Qingchun Lu, Mingyang Xin, Qian Guo, Brad S. Rothberg, Ana M. Gamero and Ling Yang

Non-Coding RNA 2022, 8(4), 61; https://doi.org/10.3390/ncrna8040061 - 10 Aug 2022

Cited by 1 | Viewed by 1976

Abstract

The multikinase inhibitor, sorafenib, is a first-line treatment for hepatocellular carcinoma (HCC), but its limited efficacy, drug resistance and toxicity are a concern. In this study, we investigated the role of lncRNA TP53TG1 in the efficacy of sorafenib in HCC cells. We found [...] Read more.

The multikinase inhibitor, sorafenib, is a first-line treatment for hepatocellular carcinoma (HCC), but its limited efficacy, drug resistance and toxicity are a concern. In this study, we investigated the role of lncRNA TP53TG1 in the efficacy of sorafenib in HCC cells. We found that treatment with sorafenib increased the expression of TP53TG1 in HCC cells. Knockdown of TP53TG1 sensitized tumor cells to the antiproliferative effects of sorafenib. Furthermore, TP53TG1 knockdown had an additive inhibitory effect on HCC cell proliferation and migration in the presence of sorafenib. The combination of TP53TG1 knockdown and sorafenib drastically inhibited the activation of the ERK pathway. This work demonstrates that TP53TG1 deficiency enhances the efficacy of sorafenib in HCC. Combining TP53TG1 knockdown with sorafenib may be an optimal form of therapy for HCC treatment. Full article

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

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Review

Jump to: Research, Other

13 pages, 718 KiB

Open AccessReview

Impacts of MicroRNA-483 on Human Diseases

by Katy Matson, Aaron Macleod, Nirali Mehta, Ellie Sempek and Xiaoqing Tang

Non-Coding RNA 2023, 9(4), 37; https://doi.org/10.3390/ncrna9040037 - 28 Jun 2023

Cited by 4 | Viewed by 1700

Abstract

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression by targeting specific messenger RNAs (mRNAs) in distinct cell types. This review provides a com-prehensive overview of the current understanding regarding the involvement of miR-483-5p and miR-483-3p in various physiological and pathological [...] Read more.

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression by targeting specific messenger RNAs (mRNAs) in distinct cell types. This review provides a com-prehensive overview of the current understanding regarding the involvement of miR-483-5p and miR-483-3p in various physiological and pathological processes. Downregulation of miR-483-5p has been linked to numerous diseases, including type 2 diabetes, fatty liver disease, diabetic nephropathy, and neurological injury. Accumulating evidence indicates that miR-483-5p plays a crucial protective role in preserving cell function and viability by targeting specific transcripts. Notably, elevated levels of miR-483-5p in the bloodstream strongly correlate with metabolic risk factors and serve as promising diagnostic markers. Consequently, miR-483-5p represents an appealing biomarker for predicting the risk of developing diabetes and cardiovascular diseases and holds potential as a therapeutic target for intervention strategies. Conversely, miR-483-3p exhibits significant upregulation in diabetes and cardiovascular diseases and has been shown to induce cellular apoptosis and lipotoxicity across various cell types. However, some discrepancies regarding its precise function have been reported, underscoring the need for further investigation in this area. Full article

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

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15 pages, 2668 KiB

Open AccessReview

Long Noncoding RNA H19: A Novel Oncogene in Liver Cancer

by Yanyan Wang, Jing Zeng, Weidong Chen, Jiangao Fan, Phillip B. Hylemon and Huiping Zhou

Non-Coding RNA 2023, 9(2), 19; https://doi.org/10.3390/ncrna9020019 - 09 Mar 2023

Cited by 9 | Viewed by 2745

Abstract

Liver cancer is the second leading cause of cancer-related death globally, with limited treatment options. Recent studies have demonstrated the critical role of long noncoding RNAs (lncRNAs) in the pathogenesis of liver cancers. Of note, mounting evidence has shown that lncRNA H19, an [...] Read more.

Liver cancer is the second leading cause of cancer-related death globally, with limited treatment options. Recent studies have demonstrated the critical role of long noncoding RNAs (lncRNAs) in the pathogenesis of liver cancers. Of note, mounting evidence has shown that lncRNA H19, an endogenous noncoding single-stranded RNA, functions as an oncogene in the development and progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumors in adults. H19 can affect many critical biological processes, including the cell proliferation, apoptosis, invasion, and metastasis of liver cancer by its function on epigenetic modification, H19/miR-675 axis, miRNAs sponge, drug resistance, and its regulation of downstream pathways. In this review, we will focus on the most relevant molecular mechanisms of action and regulation of H19 in the development and pathophysiology of HCC and CCA. This review aims to provide valuable perspectives and translational applications of H19 as a potential diagnostic marker and therapeutic target for liver cancer disease. Full article

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

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Other

Jump to: Research, Review

25 pages, 1139 KiB

Open AccessSystematic Review

Diagnostic and Prognostic Value of microRNAs in Patients with Laryngeal Cancer: A Systematic Review

by Elisabetta Broseghini, Daria Maria Filippini, Laura Fabbri, Roberta Leonardi, Andi Abeshi, Davide Dal Molin, Matteo Fermi, Manuela Ferracin and Ignacio Javier Fernandez

Non-Coding RNA 2023, 9(1), 9; https://doi.org/10.3390/ncrna9010009 - 19 Jan 2023

Cited by 2 | Viewed by 2721

Abstract

Laryngeal squamous cell cancer (LSCC) is one of the most common malignant tumors of the head and neck region, with a poor survival rate (5-year overall survival 50–80%) as a consequence of an advanced-stage diagnosis and high recurrence rate. Tobacco smoking and alcohol [...] Read more.

Laryngeal squamous cell cancer (LSCC) is one of the most common malignant tumors of the head and neck region, with a poor survival rate (5-year overall survival 50–80%) as a consequence of an advanced-stage diagnosis and high recurrence rate. Tobacco smoking and alcohol abuse are the main risk factors of LSCC development. An early diagnosis of LSCC, a prompt detection of recurrence and a more precise monitoring of the efficacy of different treatment modalities are currently needed to reduce the mortality. Therefore, the identification of effective diagnostic and prognostic biomarkers for LSCC is crucial to guide disease management and improve clinical outcomes. In the past years, a dysregulated expression of small non-coding RNAs, including microRNAs (miRNAs), has been reported in many human cancers, including LSCC, and many miRNAs have been explored for their diagnostic and prognostic potential and proposed as biomarkers. We searched electronic databases for original papers that were focused on miRNAs and LSCC, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. According to the outcome, 566 articles were initially screened, of which 177 studies were selected and included in the analysis. In this systematic review, we provide an overview of the current literature on the function and the potential diagnostic and prognostic role of tissue and circulating miRNAs in LSCC. Full article

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

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