Biological functions and potential implications of circular RNAs

Circular RNAs(circRNAs) are characterized by a covalent closed-loop structure with an absence of both 5′ cap structure and 3′ polyadenylated tail. Numerous studies have found that circRNAs play an important role in various diseases and have a variety of biological regulatory mechanisms, including acting as microRNA sponges,interacting with proteins, modulating the expression of related genes and translating into peptides or proteins.CircRNAs have also been used as biomarkers for a number of diseases, which could improve clinical practice.This review summarizes the most recent advances in biogenesis and knowledge of the biological functions of circRNAs as well as the related bioinformatics databases. We specifically describe developments in understanding of circRNA functions in the field of environmental exposure-induced diseases. Finally, we focus on potential clinical implications of circRNAs to facilitate their clinical transformation into disease treatment.

Circular RNAs:Diagnostic and Therapeutic Perspectives in CNS Diseases

Circular RNAs(circRNAs)are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends.A growing body of evidence suggests that circRNAs play important roles in physiology and pathology.In particular,accumulating data on circRNA functions in various central nervous system(CNS)diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders.In this review,we focus on the regulatory and functional roles of circRNAs in CNS diseases,highlighting their diagnostic and therapeutic potential,with the aim of providing new insights into CNS diseases.

Genome-wide map of N6-methyladenosine circular RNAs identified in mice model of severe acute pancreatitis

BACKGROUND Severe acute pancreatitis(SAP)is a deadly inflammatory disease with complex pathogenesis and lack of effective therapeutic options.N6-methyladenosine(m6A)modification of circRNAs plays important roles in physiological and pathological processes.However,the roles of m6A circRNA in the pathological process of SAP remains unknown.AIM To identify transcriptome-wide map of m6A circRNAs and to determine their biological significance and potential mechanisms in SAP.METHODS The SAP in C57BL/6 mice was induced using 4%sodium taurocholate salt.The transcriptome-wide map of m6A circRNAs was identified by m6A-modified RNA immunoprecipitation sequencing.The biological significance of circRNAs with differentially expressed m6A peaks was evaluated through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis.The underlying mechanism of m6A circRNAs in SAP was analyzed by constructing of m6A circRNAmicroRNA networks.The expression of demethylases was determined by quantitative polymerase chain reaction and western blot to deduce the possible mechanism of reversible m6A process in SAP.RESULTS Fifty-seven circRNAs with differentially expressed m6A peaks were identified by m6A-modified RNA immunoprecipitation sequencing,of which 32 were upregulated and 25 downregulated.Functional analysis of these m6A circRNAs in SAP found some important pathways involved in the pathogenesis of SAP,such as regulation of autophagy and protein digestion.In m6A circRNA–miRNA networks,several important miRNAs participated in the occurrence and progression of SAP were found to bind to these m6A circRNAs,such as miR-24-3p,miR-26a,miR-92b,miR-216b,miR-324-5p and miR-762.Notably,the total m6A level of circRNAs was reduced,while the demethylase alkylation repair homolog 5 was upregulated in SAP.CONCLUSION m6A modification of circRNAs may be involved in the pathogenesis of SAP.Our findings may provide novel insights to explore the possible pathogenetic mechanism of SAP and seek new potential therapeutic targets for SAP.

Circular RNAs in pulmonary hypertension:Emerging biological concepts and potential mechanism

Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets.Using the most powerful RNA sequencing and bioinformatics techniques,a large number of circRNAs have been identified and further functional studies have been performed.It is known that circRNAs act as potential biomarkers,sponges for microRNAs(miRNAs)and RNA-binding proteins(RBPs),and regulators of mRNA transcription.They also participate in the translation of peptides or proteins.Many types of circRNAs are dysregulated in plasma or lung tissues,and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells(PAECs)and pulmonary artery smooth muscle cells(PASMCs),leading to pulmonary vascular remodeling in pulmonary hypertension(PH).One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge.However,other potential mechanisms of action of circRNAs are still being actively explored in PH.This paper presents a systematic review of the biogenesis,biological characterization,relevant underlying functions,and future perspectives for studies of circRNAs in the pathogenesis of PH.

The biogenesis,function and clinical significance of circular RNAs in breast cancer

Circular RNAs(circ RNAs)are noncoding RNAs that form covalently closed loop structures.Circ RNAs are dysregulated in cancer and play key roles in tumorigenesis,diagnosis,and tumor therapy.Circ RNAs function as competing endogenous RNAs or micro RNA sponges that regulate transcription and splicing,binding to proteins,and translation.Circ RNAs may serve as novel biomarkers for cancer diagnosis,and they show potential as therapeutic targets in cancers including breast cancer(BC).In women,BC is the most common malignant tumor worldwide and the second leading cause of cancer death.Although evidence indicates that circ RNAs play a critical role in BC,the mechanisms regulating the function of circ RNAs in BC remain poorly understood.Here,we provide literature review aiming to clarify the role of circ RNAs in BC and summarize the latest research.We provide a systematic overview of the biogenesis and biological functions of circ RNAs,elaborate on the functional roles of circ RNAs in BC,and highlight the value of circ RNAs as diagnostic and therapeutic targets in BC.

Circular RNAs in hepatocellular carcinoma:Recent advances

Circular RNAs(circRNAs)have covalently closed loop structures at both ends,exhibiting characteristics dissimilar to those of linear RNAs.Emerging evidence suggests that aberrantly expressed circRNAs play crucial roles in hepatocellular carcinoma(HCC)by affecting the proliferation,apoptosis and invasive capacity of HCC cells.Certain circRNAs may be used as biomarkers to diagnose and predict the prognosis of HCC.Therefore,circRNAs are expected to become novel biomarkers and therapeutic targets for HCC.Herein,we briefly review the characteristics and biological functions of circRNAs,focusing on their roles in HCC to provide new insights for the early diagnosis and targeted therapy of HCC.

RNA-Seq profiling of circular RNAs in human colorectal cancer 5-fluorouracil resistance and potential biomarkers

BACKGROUND Colorectal cancer(CRC)is a commonly diagnosed cancer of the digestive system worldwide.Although chemotherapeutic agents and targeted therapeutic drugs are currently available for CRC treatment,drug resistance is a problem that cannot be ignored and needs to be solved.AIM To explore the relationship between circular RNA(circRNA)and CRC drug resistance.circRNA plays a key role in the occurrence and development of cancers,but its function in the process of drug resistance has not been widely revealed.METHODS To explore the role of circRNA in 5-fluorouracil(5-Fu)resistance,we performed the circRNA expression profile in two CRC cell lines and their homologous 5-Fu resistant cells by high-throughput sequencing.RESULTS We validated the differentially expressed circRNAs in other two paired CRC cells,confirmed that circ_0002813 and circ_0000236 could have a potential competitive endogenous RNA mechanism and be involved in the formation of 5-Fu resistance.And we combined the sequencing results of mRNA to construct the regulatory network of circRNA-miRNA-mRNA.CONCLUSION Our study revealed that circ_0002813 and circ_0000236 may as the biomarkers to predict the occurrence of 5-Fu resistance in CRC.

A potential role of circular RNAs in bone destruction of rheumatoid arthritis

Bone destruction in rheumatoid arthritis(RA)is a pathological state that always accompanies the development of RA patients,which will cause severe deformation of their joints and decline in quality of life.Circular RNAs(circRNAs)are a class of RNA molecules with circular structure,which are widely existed in a variety of organisms and play special biological functions in a variety of diseases.There has been evidence that circRNAs can act as miRNA sponges and play an important role in the treatment of bone destruction in RA.In this paper,the potential relationship between circRNAs and bone destruction in RA was discussed in terms of the regulation of cell apoptosis,osteoblast and osteoclast differentiation,and the regulation of immune inflammation,so as to provide a new approach for studying the potential mechanism of bone destruction in RA and possible therapeutic methods.

Emerging roles of circular RNAs in retinal diseases

Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina.Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration.In this review,we explore a relatively new field of research involving circular RNAs,whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged.While knowledge of circular RNAs function is limited given its novelty,current evidence has highlighted their roles as modulators of microRNAs,regulators of gene transcription,and biomarkers of disease development and progression.Here,we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy,glaucoma,proliferative vitreoretinopathy,and age-related macular degeneration.Further,we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases.

Biological roles and potential clinical values of circular RNAs in gastrointestinal malignancies

Circular RNAs(circ RNAs),a class of endogenous RNA molecules,are produced by alternative splicing of precursor RNA and are covalently linked at the 5′and 3′ends.Recent studies have revealed that dysregulated circ RNAs are closely related to the occurrence and progression of gastrointestinal malignancies.Accumulating evidence indicates that circ RNAs,including circ PVT1,circ LARP4,circ-SFMBT2,cir-ITCH,circ RNA_100782,circ_100395,circ-DONSON,hsa_circ_0001368,circ NRIP1,circ FAT1(e2),circ CCDC66,circ SMARCA5,circ-ZNF652,and circ_0030235 play important roles in the proliferation,differentiation,invasion,and metastasis of cancer cells through a variety of mechanisms,such as acting as micro RNA sponges,interacting with RNA-binding proteins,regulating gene transcription and alternative splicing,and being translated into proteins.With the characteristics of high abundance,high stability,extensive functions,and certain tissue-,time-and diseasespecific expressions,circ RNAs are expected to provide novel perspectives for the diagnoses and treatments of gastrointestinal malignancies.

Circular RNAs:new biomarkers of chemoresistance in cancer

Chemotherapeutics are validated conventional treatments for patients with advanced cancer.However,with continual application of chemotherapeutics,chemoresistance,which is often predictive of poor prognosis,has gradually become a concern in recent years.Circular RNAs(circ RNAs),a class of endogenous noncoding RNAs(nc RNAs)with a closed-loop structure,have been reported to be notable targets and markers for the prognosis,diagnosis,and treatment of many diseases,particularly cancer.Although dozens of studies have shown that circ RNAs play major roles in drug-resistance activity in tumors,the mechanisms by which circ RNAs affect chemoresistance have yet to be explored.In this review,we describe the detailed mechanisms of circ RNAs and chemotherapeutics in various cancers and summarize potential therapeutic targets for drug-resistant tumors.

Role of circular RNAs in gastrointestinal tumors and drug resistance

The incidence of gastrointestinal cancers has increased significantly over the past decade and gastrointestinal malignancies now rank among the leading causes of mortality globally.Although newer therapeutic strategies such as targeted therapies have greatly improved patient outcomes,their clinical success is limited by drug resistance,treatment failure and recurrence of metastatic disease.Therefore,there is an urgent need for further research identifying accurate and reliable biomarkers for precise treatment strategies.Circular RNAs(circRNAs)exhibit a covalently closed structure,high stability and biological conservation,and their expression is associated with the occurrence and development of gastrointestinal tumors.Moreover,circRNAs may significantly influence drug resistance of gastrointestinal cancers.In this article,we review the role of circRNAs in the occurrence and development of gastrointestinal cancer,their association with drug resistance,and potential application for early diagnosis,treatment and prognosis in gastrointestinal malignancies.Furthermore,we summarize characteristics of circRNA,including mechanism of formation and biological effects via mRNA sponging,chromatin replication,gene regulation,translational modification,signal transduction,and damage repair.Finally,we discuss whether circRNA-related noninvasive testing may be clinically provided in the future.This review provides new insights for the future development of diagnostics and therapeutics based on circRNAs in gastrointestinal tumors.

Epithelial-mesenchymal transition-related circular RNAs in lung carcinoma

The epithelial-mesenchymal transition(EMT)is a highly complex phenotypic conversion during embryogenesis,and is important for metastasis,which contributes to tumor deterioration and poor prognoses of cancer patients.Lung carcinoma has a high tendency to develop the EMT.Circular RNAs(circ RNAs)are involved in EMT-related cell invasion and metastasis in various types of cancers.Moreover,circ RNAs have been found to be a link to EMT-related transcription factors and EMT-associated signaling pathways.This review mainly focuses on the influence of EMT-related circ RNAs on lung carcinomas.More specifically,the roles of EMT-inducingand EMT-suppressive circ RNAs in lung carcinomas are discussed.With circ RNAs potentially becoming promising biomarkers and therapeutic targets for cancer managements,they will hopefully stimulate the interest of medical workers in the early diagnosis,personalized treatment,and positive prognoses in the era of precision oncology.

Current research on circular RNAs and their potential clinical implications in breast cancer

Breast cancer(BC)is one of the most common cancers and the leading causes of death among women worldwide,and its morbidity rate is growing.Discovery of novel biomarkers is necessary for early BC detection,treatment,and prognostication.Circular RNAs(circ RNAs),a novel type of endogenous non-coding RNAs with covalently closed continuous loops,have been found to have a crucial role in tumorigenesis.Studies have demonstrated that circ RNAs are aberrantly expressed in the tumor tissues and plasma of patients with BC,and they modulate gene expression affecting the proliferation,metastasis,and chemoresistance of BC by specifically binding and regulating the expression of micro RNAs(mi RNAs).Therefore,circ RNAs can be used as novel potential diagnostic and prognostic markers,and therapeutic targets for BC.This article summarizes the properties,functions,and regulatory mechanisms of circ RNAs,particularly current research on their association with BC proliferation,metastasis,and chemoresistance.

Non-coding RNAs in acute ischemic stroke:from brain to periphery

Acute ischemic stroke is a clinical emergency and a condition with high morbidity,mortality,and disability.Accurate predictive,diagnostic,and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined.With innovations in high-throughput gene sequencing analysis,many aberrantly expressed non-coding RNAs(ncRNAs)in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models.Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes,leading to neuroprotection or deterioration,thus ncRNAs can serve as therapeutic targets in acute ischemic stroke.Moreover,distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction,diagnosis,and prognosis.In particular,ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke.In this review,we consolidate the latest progress of research into the roles of ncRNAs(microRNAs,long ncRNAs,and circular RNAs)in the pathological processes of acute ischemic stroke–induced brain damage,as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction,diagnosis,and prognosis.Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke.

Emerging roles of circular RNAs in stem cells

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that widely exist in eukaryotes. As a new focus in the field of molecular regulation, circRNAs have attracted much attention in recent years. Previous studies have confirmed that circRNAs are associated with many physiological and pathological processes. CircRNAs also participate in the regulation of stem cells. Stem cells have the properties of self-renewal and differentiation, which make stem cell therapy popular. CircRNAs may serve as new targets in stem cell therapy due to their regulation in stem cells. However, the underlying relationships between circRNAs and stem cells are still being explored. In this review, we briefly summarize the effects of circRNAs on stem cells, in the context of biological activities, aging and apoptosis, and aberrant changes. Moreover, we also examine the biological roles of stem cell-derived exosomal circRNAs. We believe our review will provide insights into the effects of circRNAs on stem cells.

Multi-omics of Circular RNAs and Their Responses to Hormones in Moso Bamboo(Phyllostachys edulis)

Circular RNAs(circRNAs)are endogenous non-coding RNAs with covalently closed structures,which have important functions in plants.However,their biogenesis,degradation,and function upon treatment with gibberellins(GAs)and auxins(1-naphthaleneacetic acid,NAA)remain unknown.Here,we systematically identified and characterized the expression patterns,evolutionary conservation,genomic features,and internal structures of circRNAs using RNase R-treated libraries from moso bamboo(Phyllostachys edulis)seedlings.Moreover,we investigated the biogenesis of circRNAs dependent on both cis-and trans-regulation.We explored the function of circRNAs,including their roles in regulating microRNA(miRNA)-related genes and modulating the alternative splicing of their linear counterparts.Importantly,we developed a customized degradome sequencing approach to detect miRNA-mediated cleavage of circRNAs.Finally,we presented a comprehensive view of the participation of circRNAs in the regulation of hormone metabolism upon treatment of bamboo seedlings with GA and NAA.Collectively,our study provides insights into the biogenesis,function,and miRNA-mediated degradation of circRNAs in moso bamboo.

Emerging roles and potential clinical applications of translatable circular RNAs in cancer and other human diseases

Circular RNAs (circRNAs) are a special class of single-stranded RNA molecules with covalently closed loops widely expressed in eukaryotic organisms. CircRNAs have long been considered to play important roles in various physiological and pathological processes as non-coding RNAs. However, circRNAs have recently garnered considerable attention due to their ability to be translated into peptides/proteins via internal ribosome entry site- or N6-methyladenosine-mediated pathways or rolling translation mechanisms. Furthermore, dysregulation of translatable circRNAs and their encoded proteins has been associated with developing and progressing diseases such as cancer. This review aims to summarize the driving mechanisms of circRNA translation and the available strategies in circRNA translation research. The main focus is on the emerging biological functions of translatable circRNAs, their regulatory mechanisms, and potential clinical applications in human diseases to provide new perspectives on disease diagnosis, prognosis, and targeted therapy.

Critical involvement of circular RNAs in virus-associated cancers

Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV), Epstein–Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T-lymphotropic virus (HTLV), and Merkel cell polyomavirus (MCV)) that infect humans have been identified as an oncogene and have been associated with several human malignancies. Recently, growing attention has been attracted to exploring the pathogenesis of virus-related cancers. One of the most mysterious molecules involved in carcinogenesis and progression of virus-related cancers is circular RNAs (circRNA). These emerging non-coding RNAs (ncRNAs), due to the absence of 5′ and 3′ ends, have high stability than linear RNAs and are found in some species across the eukaryotic organisms. Compelling evidence has revealed that viruses also encode a repertoire of circRNAs, as well as dysregulation of these viral circRNAs play a critical role in the pathogenesis and progression of different types of virus-related cancers. Therefore, understanding the exact role and function of the virally encoded circRNAs with virus-associated cancers will open a new road for increasing our knowledge about the RNA world. Hence, in this review, we will focus on emerging roles of virus-encoded circRNAs in multiple cancers, including cervical cancer, gastric cancer, Merkel cell carcinoma, nasopharyngeal carcinoma, Kaposi cancer, and liver cancer.

Dysregulation of circular RNAs in inflammation and cancers

Emerging lines of evidence have shown that the production of the covalently closed single-stranded circular RNAs is not splicing errors,but rather a regulated process with distinct biogenesis and turnover.Circular RNAs are expressed in a cell type-and tissue-specific manner and often localize to specific subcellular regions or organelles for functions.The dysregulation of circular RNAs from birth to death is linked to the pathogenesis and progression of diverse diseases.This review outlines how aberrant circular RNA biogenesis,subcellular location,and degradation are linked to disease progression,focusing on metaflammation and cancers.We also discuss potential therapeutic strategies and obstacles in targeting such disease-related circular RNAs.