Comprehensive landscape and future perspectives of circular RNAs in colorectal cancer

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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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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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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P5398CircRNAs deregulation in heart failure patients

European Heart Journal ◽

10.1093/eurheartj/ehz746.0358 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Greco ◽

A Made' ◽

M Longo ◽

R Tikhomirov ◽

S Castelvecchio ◽

...

Keyword(s):

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Functional Characterization ◽

Enrichment Analysis ◽

Host Gene ◽

Circular Rnas ◽

Amplification Efficiency ◽

Rna Seq ◽

Bioinformatics Pipeline

Abstract Background Circular RNAs (circRNAs) are an emerging class of noncoding RNAs stemming from the splicing and circularization of pre-mRNAs exons. CircRNAs can regulate transcription and splicing, sequester microRNAs acting as “sponge” and inducing the respective targets, and bind to RNA binding proteins. Recently, they have been found deregulated in dilated cardiomyopathies (DCM), one of the cardiovascular diseases with the worst rate of morbidity and mortality, and whose molecular mechanisms are only partially known. Purpose Therein, we will evaluate in ischemic DCM patients the modulation of 17 circRNAs, 14 out of them obtained from literature data on DCM ischemic or not, while the other 3 were circRNAs not characterized in the heart previously. The study aims to identify circRNAs candidates for further functional characterization in DCM. In addition, as differential expression (DE) analysis is not easily performed for circRNAs in RNA-seq datasets, the validated circRNAs will be used to set up the most specific and sensitive bioinformatics pipeline for circRNA-DE analysis. Methods We designed divergent and convergent specific primers for 17 circRNAs and their host gene, respectively, and their amplification efficiency was measured by RT-qPCR. Transcripts expression was measured in left ventricle biopsies of 12 patients affected by non end-stage ischemic HF and of 12 matched controls. Results We identified cPVT1, cANKRD17, cBPTF as DE, and validated the modulation of 5 out of the 14 DCM-related circRNAs (cHIPK3, cALPK2, cPCMTD1, cNEBL, cSLC8A1), while cPDRM5, cTTN1 showed opposite modulation, which may be due to the specific disease condition. All of them were modulated differently from the respective host gene. CircRNA/miRNA interactions were predicted using Starbase 3.0. Next, mRNAs-targets of the identified miRNAs were predicted by mirDIP 4.1 and intersected with gene expression datasets of the same patients, previously obtained by microarray analysis. We found that cBPTF and cANKRD17 might sponge 12 and 2 miRNAs, respectively. Enrichment analysis of the relevant targets identified several important pathways implicated in DCM, such as MAPK, FoxO, EGFR, VEGF and Insulin/IGF pathways. In addition, deep RNA-Seq analysis that is currently ongoing and the validated circRNAs will be used to optimize the bioinformatics pipeline for circRNA DE analysis. Conclusions We identified a subset of circRNAs deregulated in ischemic HF potentially implicated in HF pathogenesis.

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RNA Dynamics in Alzheimer’s Disease

Molecules ◽

10.3390/molecules26175113 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5113

Author(s):

Agnieszka Rybak-Wolf ◽

Mireya Plass

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Rna Binding ◽

Neurodegenerative Disorder ◽

Rna Binding Proteins ◽

Current Evidence ◽

Circular Rnas ◽

Rna Dynamics ◽

Age Related

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.

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Identification of Two Novel Circular RNAs Deriving from BCL2L12 and Investigation of Their Potential Value as a Molecular Signature in Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21228867 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8867

Author(s):

Paraskevi Karousi ◽

Pinelopi I. Artemaki ◽

Christina D. Sotiropoulou ◽

Spyridon Christodoulou ◽

Andreas Scorilas ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Lines ◽

Rna Binding ◽

Rna Binding Proteins ◽

Tnm Stage ◽

Stage Ii ◽

Molecular Signature ◽

Circular Rnas ◽

Tissue Samples ◽

Related Family

The utility of circular RNAs (circRNAs) as molecular biomarkers has recently emerged. However, only a handful of them have already been studied in colorectal cancer (CRC). The purpose of this study was to identify new circRNAs deriving from BCL2L12, a member of the BCL2 apoptosis-related family, and investigate their potential as biomarkers in CRC. Total RNA extracts from CRC cell lines and tissue samples were reversely transcribed. By combining PCR with divergent primers and nested PCR followed by Sanger sequencing, we were able to discover two BCL2L12 circRNAs. Subsequently, bioinformatical tools were used to predict the interactions of these circRNAs with microRNAs (miRNAs) and RNA-binding proteins (RBPs). Following a PCR-based pre-amplification, real-time qPCR was carried out for the quantification of each circRNA in CRC samples and cell lines. Biostatistical analysis was used to assess their potential prognostic value in CRC. Both novel BCL2L12 circRNAs likely interact with particular miRNAs and RBPs. Interestingly, circ-BCL2L12-2 expression is inversely associated with TNM stage, while circ-BCL2L12-1 overexpression is associated with shorter overall survival in CRC, particularly among TNM stage II patients. Overall, we identified two novel BCL2L12 circRNAs, one of which can further stratify TNM stage II patients into two subgroups with substantially distinct prognosis.

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Circular RNAs: Biogenesis, Mechanism, and Function in Human Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms20163926 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3926 ◽

Cited By ~ 25

Author(s):

Xing Zhao ◽

Yujie Cai ◽

Jianzhen Xu

Keyword(s):

Noncoding Rna ◽

Binding Proteins ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cancer Development ◽

Circular Rnas ◽

Open Questions ◽

Circular Configuration ◽

And Function

CircRNAs are a class of noncoding RNA species with a circular configuration that is formed by either typical spliceosome-mediated or lariat-type splicing. The expression of circRNAs is usually abnormal in many cancers. Several circRNAs have been demonstrated to play important roles in carcinogenesis. In this review, we will first provide an introduction of circRNAs biogenesis, especially the regulation of circRNA by RNA-binding proteins, then we will focus on the recent findings of circRNA molecular mechanisms and functions in cancer development. Finally, some open questions are also discussed.

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Comprehensive Characterization of Androgen-Responsive circRNAs in Prostate Cancer

Life ◽

10.3390/life11101096 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1096

Author(s):

Zhe Kong ◽

Yali Lu ◽

Xuechao Wan ◽

Jun Luo ◽

Dujian Li ◽

...

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rnas ◽

Transcriptional Level ◽

The Novel ◽

Cancer Tissues ◽

Posttranscriptional Level

The androgen receptor (AR) signaling pathway plays an important role in the initiation and progression of prostate cancer. Circular RNAs (circRNAs), the novel noncoding RNAs without 5′ to 3′ polarity or 3′ poly (A), play an important role in multiple diseases. However, the potential roles of androgen-responsive circRNAs in prostate cancer remain unclear. In this study, we identified 3237 androgen-responsive circRNAs and 1954 androgen-responsive mRNAs after dihydrotestosterone (DHT) stimulation using microarray. Among them, the expression of 1296 androgen-responsive circRNAs was consistent with that of their parent genes, and we thought AR might regulate the expression of these circRNAs at the transcriptional level. In addition, 1941 circRNAs expression was not consistent with their parent genes, and we speculated that AR may regulate the expression of those circRNAs at the posttranscriptional level through affecting alternative splicing. Analyzing the androgen-responsive circRNAs regulated at the posttranscriptional level, we identified two key RNA binding proteins (RBPs), WTAP and TNRC6, using the circInteractome database, which may play important role in the biogenesis of androgen-responsive circRNAs. Furthermore, we explored the potential biological functions and predicted the molecular mechanisms of two dysregulated circRNAs (circNFIA and circZNF561) in prostate cancer. In this study, we revealed that circNFIA was upregulated in prostate cancer tissues and plasma samples from patients with prostate cancer; circNFIA may play an oncogenic role in prostate cancer. In contrast, circZNF561 was downregulated and may act as a tumor suppressor in prostate cancer. Our results suggest that androgen-responsive circRNAs might regulate the progression of prostate cancer and could be novel diagnostic biomarkers.

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Insights Into circRNAs: Functional Roles in Lung Cancer Management and the Potential Mechanisms

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.636913 ◽

2021 ◽

Vol 9 ◽

Author(s):

Bing Feng ◽

Hao Zhou ◽

Ting Wang ◽

Xinrong Lin ◽

Yongting Lai ◽

...

Keyword(s):

Lung Cancer ◽

Rna Binding ◽

Rna Binding Proteins ◽

Large Body ◽

Circular Rnas ◽

Functional Roles ◽

Cancer Management ◽

Novel Biomarkers ◽

Mirna Sponges ◽

Underlying Mechanisms

Lung cancer is the most prevalent cancer globally. It is also the leading cause of cancer-related death because of the late diagnosis and the frequent resistance to therapeutics. Therefore, it is impending to identify novel biomarkers and effective therapeutic targets to improve the clinical outcomes. Identified as a new class of RNAs, circular RNAs (circRNAs) derive from pre-mRNA back splicing with considerable stability and conservation. Accumulating research reveal that circRNAs can function as microRNA (miRNA) sponges, regulators of gene transcription and alternative splicing, as well as interact with RNA-binding proteins (RBPs), or even be translated into proteins directly. Currently, a large body of circRNAs have been demonstrated differentially expressed in physiological and pathological processes including cancer. In lung cancer, circRNAs play multiple roles in carcinogenesis, development, and response to different therapies, indicating their potential as diagnostic and prognostic biomarkers as well as novel therapeutics. In this review, we summarize the multi-faceted functions of circRNAs in lung cancer and the underlying mechanisms, together with the possible future of these discoveries in clinical application.

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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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Multifaceted Regulation of MicroRNA Biogenesis: Essential Roles and Functional Integration in Neuronal and Glial Development

International Journal of Molecular Sciences ◽

10.3390/ijms22136765 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6765

Author(s):

Izabela Suster ◽

Yue Feng

Keyword(s):

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Functional Integration ◽

Mirna Biogenesis ◽

Circular Rnas ◽

Mirna Processing ◽

Endogenous Gene ◽

Processing Enzymes ◽

Non Coding Rnas

MicroRNAs (miRNAs) are small, non-coding RNAs that function as endogenous gene silencers. Soon after the discovery of miRNAs, a subset of brain-enriched and brain-specific miRNAs were identified and significant advancements were made in delineating miRNA function in brain development. However, understanding the molecular mechanisms that regulate miRNA biogenesis in normal and diseased brains has become a prevailing challenge. Besides transcriptional regulation of miRNA host genes, miRNA processing intermediates are subjected to multifaceted regulation by canonical miRNA processing enzymes, RNA binding proteins (RBPs) and epitranscriptomic modifications. Further still, miRNA activity can be regulated by the sponging activity of other non-coding RNA classes, namely circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Differential abundance of these factors in neuronal and glial lineages partly underlies the spatiotemporal expression and function of lineage-specific miRNAs. Here, we review the continuously evolving understanding of the regulation of neuronal and glial miRNA biogenesis at the transcriptional and posttranscriptional levels and the cooperativity of miRNA species in targeting key mRNAs to drive lineage-specific development. In addition, we review dysregulation of neuronal and glial miRNAs and the detrimental impacts which contribute to developmental brain disorders.

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