Protein-Related Circular RNAs in Human Pathologies

Circular RNAs (circRNAs) are a distinct family of RNAs derived from alternative splicing which play a crucial role in regulating gene expression by acting as microRNA (miRNA) and RNA binding protein (RBP) sponges. However, recent studies have also reported the multifunctional potential of these particles. Under different conditions, circRNAs not only regulate protein synthesis, destination, and degradation but can serve as protein scaffolds or recruiters and are also able to produce short peptides with active biological functions. circRNAs are under ongoing investigation because of their close association with the development of diseases. Some circRNAs are reportedly expressed in a tissue- and development stage-specific manner. Furthermore, due to other features of circRNAs, including their stability, conservation, and high abundance in bodily fluids, they are believed to be potential biomarkers for various diseases, including cancers. In this review, we focus on providing a summary of the current knowledge on circRNA–protein interactions. We present the properties and functions of circRNAs, the possible mechanisms of their translation abilities, and the emerging functions of circRNA-derived peptides in human pathologies.

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The Regulatory Functions of Circular RNAs in Digestive System Cancers

Cancers ◽

10.3390/cancers12030770 ◽

2020 ◽

Vol 12 (3) ◽

pp. 770 ◽

Cited By ~ 4

Author(s):

Xiao Yuan ◽

Ya Yuan ◽

Zhi He ◽

Diyan Li ◽

Bo Zeng ◽

...

Keyword(s):

Digestive System ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rna ◽

Research Progress ◽

Circular Rnas ◽

Biological Functions ◽

Ribonucleic Acids ◽

Mirna Sponges ◽

And Biological Markers

Circular ribonucleic acids (circRNAs), which are a type of covalently closed circular RNA, are receiving increasing attention. An increasing amount of evidence suggests that circRNAs are involved in the biogenesis and development of multiple diseases such as digestive system cancers. Dysregulated circRNAs have been found to act as oncogenes or tumour suppressors in digestive system cancers. Moreover, circRNAs are related to ageing and a wide variety of processes in tumour cells, such as cell apoptosis, invasion, migration, and proliferation. Moreover, circRNAs can perform a remarkable multitude of biological functions, such as regulating splicing or transcription, binding RNA-binding proteins to enable function, acting as microRNA (miRNA) sponges, and undergoing translated into proteins. However, in digestive system cancers, circRNAs function mainly as miRNA sponges. Herein, we summarise the latest research progress on biological functions of circRNAs in digestive system cancers. This review serves as a synopsis of potential therapeutic targets and biological markers for digestive system cancer.

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circRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications

Cells ◽

10.3390/cells9030659 ◽

2020 ◽

Vol 9 (3) ◽

pp. 659 ◽

Cited By ~ 9

Author(s):

Mohamed Zaiou

Keyword(s):

Diabetes Mellitus ◽

Rna Binding ◽

Rna Binding Proteins ◽

Current Knowledge ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Future Research ◽

Circular Rnas ◽

Obesity Hypertension ◽

Based Medicine

Circular RNAs (circRNAs) belong to the ever-growing class of naturally occurring noncoding RNAs (ncRNAs) molecules. Unlike linear RNA, circRNAs are covalently closed transcripts mostly generated from precursor-mRNA by a non-canonical event called back-splicing. They are highly stable, evolutionarily conserved, and widely distributed in eukaryotes. Some circRNAs are believed to fulfill a variety of functions inside the cell mainly by acting as microRNAs (miRNAs) or RNA-binding proteins (RBPs) sponges. Furthermore, mounting evidence suggests that the misregulation of circRNAs is among the first alterations in various metabolic disorders including obesity, hypertension, and cardiovascular diseases. More recent research has revealed that circRNAs also play a substantial role in the pathogenesis of diabetes mellitus (DM) and related vascular complications. These findings have added a new layer of complexity to our understanding of DM and underscored the need to reexamine the molecular pathways that lead to this disorder in the context of epigenetics and circRNA regulatory mechanisms. Here, I review current knowledge about circRNAs dysregulation in diabetes and describe their potential role as innovative biomarkers to predict diabetes-related cardiovascular (CV) events. Finally, I discuss some of the actual limitations to the promise of these RNA transcripts as emerging therapeutics and provide recommendations for future research on circRNA-based medicine.

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Structure and properties of the Ca2+-binding CUB domain, a widespread ligand-recognition unit involved in major biological functions

Biochemical Journal ◽

10.1042/bj20111027 ◽

2011 ◽

Vol 439 (2) ◽

pp. 185-193 ◽

Cited By ~ 30

Author(s):

Christine Gaboriaud ◽

Lynn Gregory-Pauron ◽

Florence Teillet ◽

Nicole M. Thielens ◽

Isabelle Bally ◽

...

Keyword(s):

Binding Site ◽

Protein Interactions ◽

Current Knowledge ◽

Density Lipoprotein ◽

Extracellular Proteins ◽

Present Review ◽

Biological Functions ◽

Protein Motifs ◽

Wide Range ◽

Cub Domain

CUB domains are 110-residue protein motifs exhibiting a β-sandwich fold and mediating protein–protein interactions in various extracellular proteins. Recent X-ray structural and mutagenesis studies have led to the identification of a particular CUB domain subset, cbCUB (Ca2+-binding CUB domain). Unlike other CUB domains, these harbour a homologous Ca2+-binding site that underlies a conserved binding site mediating ionic interaction between two of the three conserved acidic Ca2+ ligands and a basic (lysine or arginine) residue of a protein ligand, similar to the interactions mediated by the low-density lipoprotein receptor family. cbCUB-mediated protein–ligand interactions usually involve multipoint attachment through several cbCUBs, resulting in high-affinity binding through avidity, despite the low affinity of individual interactions. The aim of the present review is to summarize our current knowledge about the structure and functions of cbCUBs, which represent the majority of the known CUB repertoire and are involved in a variety of major biological functions, including immunity and development, as well as in various cancer types. Examples discussed in the present review include a wide range of soluble and membrane-associated human proteins, as well as some archaeal and invertebrate proteins. The fact that these otherwise unrelated proteins share a common Ca2+-dependent ligand-binding ability suggests a mechanism inheri-ted from very primitive ancestors. The information provided in the present review should stimulate further investigations on the crucial interactions mediated by cbCUB-containing proteins.

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Circ-0000284 arouses malignant phenotype of cholangiocarcinoma cells and regulates the biological functions of peripheral cells through cellular communication

Clinical Science ◽

10.1042/cs20190589 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1935-1953 ◽

Cited By ~ 14

Author(s):

Shuming Wang ◽

Yilin Hu ◽

Xiurui Lv ◽

Bin Li ◽

Dianhua Gu ◽

...

Keyword(s):

Cell Lines ◽

Rna Binding ◽

Direct Interaction ◽

Luciferase Reporter ◽

Circular Rnas ◽

Biological Functions ◽

Normal Cells ◽

Cholangiocarcinoma Cell

Abstract Circular RNAs (circRNAs) play a vital role in cancers. Accumulated evidences showed that the physiological condition of cells can be reflected by the circRNAs in the exosomes they secrete, and these exosomal circRNAs can be captured by the receptor cells, thereby inducing a series of cellular responses. We performed qRT-PCR to detect the expression level of circ-0000284 in cholangiocarcinoma cell lines, tissues and plasma exosomes. Then the direct interaction between circ-0000284 and miR-637 was investigated through dual-luciferase reporter assay, RNA binding protein immunoprecipitation (RIP) assay and Fluorescent in situ hybridization (FISH) assay. Subsequently, EdU (5-ethynyl-2′-deoxyuridine), migration, invasion assay, flow cytometry and nude mouse tumorigenicity assay were adopted to evaluate the effect of circ-0000284 on migration, invasion, proliferation and apoptosis of cholangiocarcinoma cells. Additionally, TEM was conducted to investigate the shape and size of exosomes from cholangiocarcioma and 293T cell lines. Circ-0000284 was evidently elevated in cholangiocarcinoma cell lines, tumor tissues and plasma exosomes. Meanwhile, the high expression of circ-0000284 enhanced the migration, invasion and proliferation abilities of cholangiocarcinoma cells in vivo and in vitro. Besides, the levels of circ-0000284 were increased in cholangiocarcinoma cells and exosomes from them. Moreover, exosomes from cholangiocarcinoma cells enhanced circ-0000284 expression and stimulated migration and proliferation of the surrounding normal cells. Our findings suggest that on the one hand circ-0000284 functions as a competitive endogenous RNA to promote cholangiocarcinoma progression, and on the other hand, circ-0000284 can be directly transferred from cholangiocarcinoma cells to surrounding normal cells via exosomes and in this way regulate the biological functions of surrounding normal cells.

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Dissecting the Role of Circular RNAs in Sarcomas with Emphasis on Osteosarcomas

Biomedicines ◽

10.3390/biomedicines9111642 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1642

Author(s):

Eleftheria Lakiotaki ◽

Dimitrios S. Kanakoglou ◽

Andromachi Pampalou ◽

Eleni A. Karatrasoglou ◽

Christina Piperi ◽

...

Keyword(s):

Protein Interactions ◽

Rna Binding ◽

Malignant Tumors ◽

Kaposi Sarcoma ◽

Metastatic Potential ◽

Circular Rnas ◽

Mesenchymal Tumors ◽

Protein Coding ◽

Ongoing Research

Circular RNAs (circRNAs) are single-stranded RNAs generated from exons back-splicing from a single pre-mRNA, forming covalently closed loop structures which lack 5′-3′-polarity or polyadenylated tail. Ongoing research depicts that circRNAs play a pivotal role in tumorigenesis, tumor progression, metastatic potential and chemoresistance by regulating transcription, microRNA (miRNA) sponging, RNA-binding protein interactions, alternative splicing and to a lesser degree, protein coding. Sarcomas are rare malignant tumors stemming from mesenchymal cells. Due to their clinically insidious onset, they often present at advanced stage and their treatment may require aggressive chemotherapeutic or surgical options. This review is mainly focused on the regulatory functions of circRNAs on osteosarcoma progression and their potential role as biomarkers, an area which has prompted lately extensive research. The attributed oncogenic role of circRNAs on other mesenchymal tumors such as Kaposi Sarcoma (KS), Rhabdomyosarcoma (RMS) or Gastrointestinal Stromal Tumors (GISTs) is also described. The involvement of circRNAs on sarcoma oncogenesis and relevant emerging diagnostic, prognostic and therapeutic applications are expected to gain more research interest in the future.

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Emerging Role of Circular RNA–Protein Interactions

Non-Coding RNA ◽

10.3390/ncrna7030048 ◽

2021 ◽

Vol 7 (3) ◽

pp. 48

Author(s):

Arundhati Das ◽

Tanvi Sinha ◽

Sharmishtha Shyamal ◽

Amaresh Chandra Panda

Keyword(s):

Gene Expression ◽

Protein Interactions ◽

Nuclear Export ◽

Rna Binding ◽

Rna Binding Proteins ◽

Critical Role ◽

Large Family ◽

Circular Rnas ◽

Protein Interaction Data ◽

Cell Physiology

Circular RNAs (circRNAs) are emerging as novel regulators of gene expression in various biological processes. CircRNAs regulate gene expression by interacting with cellular regulators such as microRNAs and RNA binding proteins (RBPs) to regulate downstream gene expression. The accumulation of high-throughput RNA–protein interaction data revealed the interaction of RBPs with the coding and noncoding RNAs, including recently discovered circRNAs. RBPs are a large family of proteins known to play a critical role in gene expression by modulating RNA splicing, nuclear export, mRNA stability, localization, and translation. However, the interaction of RBPs with circRNAs and their implications on circRNA biogenesis and function has been emerging in the last few years. Recent studies suggest that circRNA interaction with target proteins modulates the interaction of the protein with downstream target mRNAs or proteins. This review outlines the emerging mechanisms of circRNA–protein interactions and their functional role in cell physiology.

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Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

10.1101/2020.03.19.997478 ◽

2020 ◽

Author(s):

Trine Line Hauge Okholm ◽

Shashank Sathe ◽

Samuel S. Park ◽

Andreas Bjerregaard Kamstrup ◽

Asta Mannstaedt Rasmussen ◽

...

Keyword(s):

Bladder Cancer ◽

Protein Interactions ◽

Binding Sites ◽

Target Genes ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rna ◽

Circular Rnas ◽

Cancer Genes

AbstractCircular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA binding proteins (RBPs), however, little is known about the prevalence and strength of these interactions in different biological contexts. Here, we comprehensively evaluate the interplay between circRNAs and RBPs in the ENCODE cell lines, HepG2 and K562, by profiling the expression of circRNAs in fractionated total RNA-sequencing samples and analyzing binding sites of 150 RBPs in large eCLIP data sets. We show that KHSRP binding sites are enriched in flanking introns of circRNAs in both HepG2 and K562 cells, and that KHSRP depletion affects circRNA biogenesis. Additionally, we show that exons forming circRNAs are generally enriched with RBP binding sites compared to non-circularizing exons. To detect individual circRNAs with regulatory potency, we computationally identify circRNAs that are highly covered by RBP binding sites and experimentally validate circRNA-RBP interactions by RNA immunoprecipitations. We characterize circCDYL, a highly expressed circRNA with clinical and functional implications in bladder cancer, which is covered with GRWD1 binding sites. We confirm that circCDYL binds GRWD1 in vivo and functionally characterizes the effect of circCDYL-GRWD1 interactions on target genes in HepG2. Furthermore, we confirm interactions between circCDYL and RBPs in bladder cancer cells and demonstrate that circCDYL depletion affects hallmarks of cancer and perturbs the expression of key cancer genes, e.g. TP53 and MYC. Finally, we show that elevated levels of highly RBP-covered circRNAs, including circCDYL, are associated with overall survival of bladder cancer patients. Our study demonstrates transcriptome-wide and cell-type-specific circRNA-RBP interactions that could play important regulatory roles in tumorigenesis.

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Circular RNA and Diabetes: Epigenetic Regulator with Diagnostic Role

Current Molecular Medicine ◽

10.2174/1566524020666200129142106 ◽

2020 ◽

Vol 20 (7) ◽

pp. 516-526 ◽

Cited By ~ 11

Author(s):

Kazem Abbaszadeh-Goudarzi ◽

Shabnam Radbakhsh ◽

Mohammad Hossein Pourhanifeh ◽

Hashem Khanbabaei ◽

Amirhosein Davoodvandi ◽

...

Keyword(s):

Rna Binding ◽

Close Relation ◽

Circular Rna ◽

Circular Rnas ◽

Genes Expression ◽

Epigenetic Regulator ◽

Specific Manner ◽

Diagnostic Role ◽

Microrna Sponge ◽

Non Coding Rnas

Circular RNAs, a group of endogenous non-coding RNAs, are characterized by covalently closed cyclic structures with no poly-adenylated tails. It has been recently recommended that cirRNAs have an essential role in regulating genes expression by functioning as a translational regulator, RNA binding protein sponge and microRNA sponge. Due to their close relation to the progression of various diseases such as diabetes, circRNAs have become a research hotspot. A number of circRNAs (i.e., circRNA_0054633, circHIPK3, circANKRD36, and circRNA11783-2) have been shown to be associated with initiation and progression of diabetes. Based on reports, in a tissue, some circRNAs are expressed in a developmental stage-specific manner. In this study, we reviewed research on circular RNAs involved in the pathogenesis and diagnosis of diabetes and their prognostic roles.

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An Overview of Circular RNAs and Their Implications in Myotonic Dystrophy

International Journal of Molecular Sciences ◽

10.3390/ijms20184385 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4385 ◽

Cited By ~ 3

Author(s):

Karol Czubak ◽

Saam Sedehizadeh ◽

Piotr Kozlowski ◽

Marzena Wojciechowska

Keyword(s):

Myotonic Dystrophy ◽

Rna Binding ◽

Rna Binding Proteins ◽

Current Knowledge ◽

Circular Rnas ◽

Contributing Factors ◽

Aberrant Expression ◽

New Members ◽

Human Disorders

Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by RNA-binding proteins. CircRNAs are abundant across eukaryotes; however, their biological functions remain largely speculative. Recently, they have been emerging as new members of a gene regulatory network and contributing factors in various human diseases including cancer, neurological, muscular and cardiovascular disorders. In this review, we present an overview of the current knowledge about circRNAs biogenesis and their aberrant expression in various human disorders. In particular, we focus on the latest discovery of circRNAs global upregulation in myotonic dystrophy type 1 (DM1) skeletal muscles and the role these prospective biomarkers might have for prognosis and therapeutic response in DM1.

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Functional Roles and Biological Mechanisms of Circular RNAs and Their Encoded Peptides in Glioma: A Narrative Review

International Clinical Neuroscience Journal ◽

10.34172/icnj.2021.33 ◽

2021 ◽

Vol 8 (4) ◽

pp. 157-167

Author(s):

Seyedeh Zahra Bakhti ◽

Sana Dadashi ◽

Anahita Dah Pahlevan ◽

Fatemeh Kafshresan

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Current Knowledge ◽

Expression Patterns ◽

Circular Rnas ◽

Specific Expression ◽

Diagnostic Biomarkers ◽

Functional Roles ◽

Non Coding Rnas ◽

Mirna Sponges

Circular RNAs (circRNAs) are a complicated class of non-coding RNAs that have a covalently closed loop structure and are very stable and cautious. Multiple biological processes of malignancy, including tumorigenesis, development, invasion, metastasis, apoptosis, and vascularization, are disrupted by an increased number of circRNAs. Recent research has showed that circRNAs, functioning as microRNA (miRNA) sponges or protein scaffolds, interacting with RNA-binding proteins (RBPs), and autophagy regulators, affect the transcription and splicing regulation. Many circRNAs have tissue-specific expression patterns and are heavily conserved. CircRNA levels in neurons are dynamically modulated. Growing evidence suggests that circRNAs are highly abundant in neural tissues, perhaps owing to the proliferation of particular genes that promote circularization, implying that circRNA dysregulation is linked to nervous system disorders including glioma. The most widespread and deadly primary malignant brain tumor is glioma. CircRNA has a close connection to glioma, according to reported research. Here, the current knowledge about the properties of circRNAs is introduced and the biological and molecular functions of circRNAs are described. Then, the clinical association of circRNAs with glioma/glioblastoma and their level of expression and their regulatory mechanisms in tumorigenesis are discussed. Moreover, the potential of circRNAs as diagnostic biomarkers and predictors of brain cancer risk and possible therapeutic targets in medicine is examined.

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