Circular RNAs as potential biomarkers and therapeutics for cardiovascular disease

Circular RNAs (circRNAs) are genetic regulators that were earlier considered as “junk”. In contrast to linear RNAs, they have covalently linked ends with no polyadenylated tails. CircRNAs can act as RNA-binding proteins, sequestering agents, transcriptional regulators, as well as microRNA sponges. In addition, it is reported that some selected circRNAs are transformed into functional proteins. These RNA molecules always circularize through covalent bonds, and their presence has been demonstrated across species. They are usually abundant and stable as well as evolutionarily conserved in tissues (liver, lung, stomach), saliva, exosomes, and blood. Therefore, they have been proposed as the “next big thing” in molecular biomarkers for several diseases, particularly in cancer. Recently, circRNAs have been investigated in cardiovascular diseases (CVD) and reported to play important roles in heart failure, coronary artery disease, and myocardial infarction. Here, we review the recent literature and discuss the impact and the diagnostic and prognostic values of circRNAs in CVD.

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The Emerging Role and Promise of Circular RNAs in Obesity and Related Metabolic Disorders

Cells ◽

10.3390/cells9061473 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1473

Author(s):

Mohamed Zaiou

Keyword(s):

Rna Binding ◽

Metabolic Diseases ◽

Rna Binding Proteins ◽

In Vivo Studies ◽

Future Research ◽

Circular Rnas ◽

Exciting Field ◽

Rna Molecules

Circular RNAs (circRNAs) are genome transcripts that are produced from back-splicing of specific regions of pre-mRNA. These single-stranded RNA molecules are widely expressed across diverse phyla and many of them are stable and evolutionary conserved between species. Growing evidence suggests that many circRNAs function as master regulators of gene expression by influencing both transcription and translation processes. Mechanistically, circRNAs are predicted to act as endogenous microRNA (miRNA) sponges, interact with functional RNA-binding proteins (RBPs), and associate with elements of the transcriptional machinery in the nucleus. Evidence is mounting that dysregulation of circRNAs is closely related to the occurrence of a range of diseases including cancer and metabolic diseases. Indeed, there are several reports implicating circRNAs in cardiovascular diseases (CVD), diabetes, hypertension, and atherosclerosis. However, there is very little research addressing the potential role of these RNA transcripts in the occurrence and development of obesity. Emerging data from in vitro and in vivo studies suggest that circRNAs are novel players in adipogenesis, white adipose browning, obesity, obesity-induced inflammation, and insulin resistance. This study explores the current state of knowledge on circRNAs regulating molecular processes associated with adipogenesis and obesity, highlights some of the challenges encountered while studying circRNAs and suggests some perspectives for future research directions in this exciting field of study.

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Circular RNAs: new genetic tools in melanoma

Biomarkers in Medicine ◽

10.2217/bmm-2019-0567 ◽

2020 ◽

Vol 14 (7) ◽

pp. 563-571 ◽

Cited By ~ 2

Author(s):

Jamal Hallajzadeh ◽

Elaheh Amirani ◽

Hamed Mirzaei ◽

Rana Shafabakhsh ◽

Seyyed M Mirhashemi ◽

...

Keyword(s):

Noncoding Rna ◽

Rna Binding ◽

New Technologies ◽

Rna Binding Proteins ◽

Circular Rnas ◽

Cancer Types ◽

Microrna Sponge ◽

The Impact ◽

Insight Into

Melanoma is the most lethal form of skin cancer. New technologies have resulted in major advances in the diagnosis and treatment of melanoma and other cancer types. Recently, some studies have investigated the role of circular RNAs (circRNAs) in different cancers. CircRNAs are a member of long noncoding RNA family mainly formed through back-splicing and have a closed-loop structure. These molecules affect several biological and oncogenic cascades in diverse ways via acting as microRNA sponge, interacting with RNA-binding proteins and acting as a transcription regulator. In this review, we made an insight into the impact of circRNA dysregulation in the melanoma tumorigenesis based on the presented evidences.

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Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

Cell & Bioscience ◽

10.1186/s13578-021-00661-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xuechai Chen ◽

Jianan Wang ◽

Muhammad Tahir ◽

Fangfang Zhang ◽

Yuanyuan Ran ◽

...

Keyword(s):

Intervertebral Disc Degeneration ◽

Rna Binding ◽

Rna Binding Proteins ◽

Degradation Process ◽

Human Diseases ◽

Rna Modification ◽

Rna Methylation ◽

M6a Rna Methylation ◽

The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

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Identification of Novel RNA Binding Proteins Influencing Circular RNA Expression in Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22147477 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7477

Author(s):

Rok Razpotnik ◽

Petra Nassib ◽

Tanja Kunej ◽

Damjana Rozman ◽

Tadeja Režen

Keyword(s):

Hepatocellular Carcinoma ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulatory Protein ◽

Circular Rna ◽

Differentially Expressed ◽

Circular Rnas ◽

Bioinformatics Analyses ◽

Published Evidence

Circular RNAs (circRNAs) are increasingly recognized as having a role in cancer development. Their expression is modified in numerous cancers, including hepatocellular carcinoma (HCC); however, little is known about the mechanisms of their regulation. The aim of this study was to identify regulators of circRNAome expression in HCC. Using publicly available datasets, we identified RNA binding proteins (RBPs) with enriched motifs around the splice sites of differentially expressed circRNAs in HCC. We confirmed the binding of some of the candidate RBPs using ChIP-seq and eCLIP datasets in the ENCODE database. Several of the identified RBPs were found to be differentially expressed in HCC and/or correlated with the overall survival of HCC patients. According to our bioinformatics analyses and published evidence, we propose that NONO, PCPB2, PCPB1, ESRP2, and HNRNPK are candidate regulators of circRNA expression in HCC. We confirmed that the knocking down the epithelial splicing regulatory protein 2 (ESRP2), known to be involved in the maintenance of the adult liver phenotype, significantly changed the expression of candidate circRNAs in a model HCC cell line. By understanding the systemic changes in transcriptome splicing, we can identify new proteins involved in the molecular pathways leading to HCC development and progression.

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Comprehensive landscape and future perspectives of circular RNAs in colorectal cancer

Molecular Cancer ◽

10.1186/s12943-021-01318-6 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Fei Long ◽

Zhi Lin ◽

Liang Li ◽

Min Ma ◽

Zhixing Lu ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rnas ◽

Future Perspectives ◽

Cis Acting ◽

New Class ◽

Functional Peptides ◽

Mirna Sponges

AbstractColorectal cancer (CRC) is a common hereditary tumor that is often fatal. Its pathogenesis involves multiple genes, including circular RNAs (circRNAs). Notably, circRNAs constitute a new class of noncoding RNAs (ncRNAs) with a covalently closed loop structure and have been characterized as stable, conserved molecules that are abundantly expressed in tissue/development-specific patterns in eukaryotes. Based on accumulating evidence, circRNAs are aberrantly expressed in CRC tissues, cells, exosomes, and blood from patients with CRC. Moreover, numerous circRNAs have been identified as either oncogenes or tumor suppressors that mediate tumorigenesis, metastasis and chemoradiation resistance in CRC. Although the regulatory mechanisms of circRNA biogenesis and functions remain fairly elusive, interesting results have been obtained in studies investigating CRC. In particular, the expression of circRNAs in CRC is comprehensively modulated by multiple factors, such as splicing factors, transcription factors, specific enzymes and cis-acting elements. More importantly, circRNAs exert pivotal effects on CRC through various mechanisms, including acting as miRNA sponges or decoys, interacting with RNA binding proteins, and even translating functional peptides. Finally, circRNAs may serve as promising diagnostic and prognostic biomarkers and potential therapeutic targets in the clinical practice of CRC. In this review, we discuss the dysregulation, functions and clinical significance of circRNAs in CRC and further discuss the molecular mechanisms by which circRNAs exert their functions and how their expression is regulated. Based on this review, we hope to reveal the functions of circRNAs in the initiation and progression of cancer and highlight the future perspectives on strategies targeting circRNAs in cancer research.

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Current Understanding of Circular RNAs in Systemic Lupus Erythematosus

Frontiers in Immunology ◽

10.3389/fimmu.2021.628872 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hongjiang Liu ◽

Yundong Zou ◽

Chen Chen ◽

Yundi Tang ◽

Jianping Guo

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Rna Binding ◽

Rna Binding Proteins ◽

Protein Complexes ◽

Expression Patterns ◽

Regulation Of Gene Expression ◽

Current Understanding ◽

Circular Rnas ◽

Systemic Lupus

Systemic lupus erythematosus (SLE) is a common and potentially fatal autoimmune disease that affects multiple organs. To date, its etiology and pathogenesis remains elusive. Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs with covalently closed loop structure. Growing evidence has demonstrated that circRNAs may play an essential role in regulation of gene expression and transcription by acting as microRNA (miRNA) sponges, impacting cell survival and proliferation by interacting with RNA binding proteins (RBPs), and strengthening mRNA stability by forming RNA-protein complexes duplex structures. The expression patterns of circRNAs exhibit tissue-specific and pathogenesis-related manner. CircRNAs have implicated in the development of multiple autoimmune diseases, including SLE. In this review, we summarize the characteristics, biogenesis, and potential functions of circRNAs, its impact on immune responses and highlight current understanding of circRNAs in the pathogenesis of SLE.

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The effective function of circular RNA in colorectal cancer

Cancer Cell International ◽

10.1186/s12935-021-02196-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mandana Ameli-Mojarad ◽

Melika Ameli-Mojarad ◽

Mahrooyeh Hadizadeh ◽

Chris Young ◽

Hosna Babini ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rna ◽

Circular Rnas ◽

Colorectal Tumorigenesis ◽

Non Coding Rnas ◽

Mirna Sponges ◽

Mechanisms Of Development

AbstractColorectal cancer (CRC) is the 3rd most common type of cancer worldwide. Late detection plays role in one-third of annual mortality due to CRC. Therefore, it is essential to find a precise and optimal diagnostic and prognostic biomarker for the identification and treatment of colorectal tumorigenesis. Covalently closed, circular RNAs (circRNAs) are a class of non-coding RNAs, which can have the same function as microRNA (miRNA) sponges, as regulators of splicing and transcription, and as interactors with RNA-binding proteins (RBPs). Therefore, circRNAs have been investigated as specific targets for diagnostic and prognostic detection of CRC. These non-coding RNAs are also linked to metastasis, proliferation, differentiation, migration, angiogenesis, apoptosis, and drug resistance, illustrating the importance of understanding their involvement in the molecular mechanisms of development and progression of CRC. In this review, we present a detailed summary of recent findings relating to the dysregulation of circRNAs and their potential role in CRC.

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Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

npj Parkinson s Disease ◽

10.1038/s41531-021-00265-9 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Epaminondas Doxakis

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rna Binding ◽

Rna Binding Proteins ◽

Clinical Manifestations ◽

Alpha Synuclein ◽

Circular Rnas ◽

Age Related ◽

And Function ◽

The Brain

AbstractParkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

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Two Yeast La Motif-containing Proteins Are RNA-binding Proteins that Associate with Polyribosomes

Molecular Biology of the Cell ◽

10.1091/mbc.10.11.3849 ◽

1999 ◽

Vol 10 (11) ◽

pp. 3849-3862 ◽

Cited By ~ 36

Author(s):

Suzanne G. Sobel ◽

Sandra L. Wolin

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Polymerase Iii ◽

Mrna Translation ◽

Protein Synthesis Inhibitors ◽

La Protein ◽

Evolutionarily Conserved ◽

Synthetically Lethal ◽

Type Strains

We have characterized two Saccharomyces cerevisiaeproteins, Sro9p and Slf1p, which contain a highly conserved motif found in all known La proteins. Originally described as an autoantigen in patients with rheumatic disease, the La protein binds to newly synthesized RNA polymerase III transcripts. In yeast, the La protein homologue Lhp1p is required for the normal pathway of tRNA maturation and also stabilizes newly synthesized U6 RNA. We show that deletions in both SRO9 and SLF1 are not synthetically lethal with a deletion in LHP1, indicating that the three proteins do not function in a single essential process. Indirect immunofluorescence microscopy reveals that although Lhp1p is primarily localized to the nucleus, Sro9p is cytoplasmic. We demonstrate that Sro9p and Slf1p are RNA-binding proteins that associate preferentially with translating ribosomes. Consistent with a role in translation, strains lacking either Sro9p or Slf1p are less sensitive than wild-type strains to certain protein synthesis inhibitors. Thus, Sro9p and Slf1p define a new and possibly evolutionarily conserved class of La motif-containing proteins that may function in the cytoplasm to modulate mRNA translation.

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