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Circular RNAs: New Insights into the Molecular Biology of Cancer
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Circular RNAs: New Insights into the Molecular Biology of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 41462

Special Issue Information

Dear Colleagues,

Circular RNAs (circRNAs) are a new RNA type, derived from back-splicing. circRNAs have peaked researchers’ interest due to their widespread expression and multifaceted role. More specifically, they can act as microRNA sponges, protein sponges or scaffolds, and encode for peptides. Additionally, they play regulatory roles in several cellular processes, including signaling and alternative splicing, both in physiological and pathological states. In particular, their expression has been associated with several aspects of cancer cell life, for instance proliferation and migration, while several studies highlight their value as cancer biomarkers and therapeutic targets. The existing findings, combined with the fact that the cancer initiation and progression mechanisms are not well understood yet, support the further investigation of circRNAs in the field of cancer pathobiology.

This Special Issue will focus on the role of circRNAs in cancer, covering molecular, cellular and (pre)clinical aspects, aiming to enlighten the implication of circRNAs in human malignancies. The authors are encouraged to submit their original research studies concerning this topic. Reviews that highlight new findings in the above areas are also welcome. Ι hope that this Special Issue regarding circRNAs in cancer will interest the readers of Cancers.

Dr. Christos K. Kontos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • RNA biology
  • circRNAs
  • human malignancies
  • therapeutic targets
  • cancer biomarkers
  • cancer progression
  • cancer initiation
  • cancer metastasis
  • cancer therapy resistance
  • regulation of signaling pathways

Published Papers (15 papers)

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Research

Jump to: Review, Other

25 pages, 5464 KiB  
Article
Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma
by Rok Razpotnik, Robert Vidmar, Marko Fonović, Damjana Rozman and Tadeja Režen
Cancers 2022, 14(18), 4524; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184524 - 19 Sep 2022
Cited by 7 | Viewed by 2306
Abstract
Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced [...] Read more.
Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced colony formation, migration, cell proliferation, sorafenib sensitivity, and additionally induced morphological changes in cell lines, indicating an important role of hsa_circ_0062682 in oncogenesis. Pathway enrichment analysis and gene set enrichment analysis of the transcriptome data from hsa_circ_0062682 knockdown explained the observed phenotypes and exposed transcription factors E2F1, Sp1, HIF-1α, and NFκB1 as potential downstream targets. Biotinylated oligonucleotide pulldown combined with proteomic analyses identified protein interaction partners of which YBX1, a known oncogene, was confirmed by RNA immunoprecipitation. Furthermore, we discovered a complex cell-type-specific phenotype in response to the oncogenic potential of hsa_circ_0062682. This finding is in line with different classes of HCC tumours, and more studies are needed to shed a light on the molecular complexity of liver cancer. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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17 pages, 12256 KiB  
Article
CircFISH: A Novel Method for the Simultaneous Imaging of Linear and Circular RNAs
by Aakash Koppula, Ahmed Abdelgawad, Jlenia Guarnerio, Mona Batish and Vijay Parashar
Cancers 2022, 14(2), 428; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020428 - 15 Jan 2022
Cited by 7 | Viewed by 2614
Abstract
Circular RNAs (circRNAs) are regulatory RNAs which have recently been shown to have clinical significance in several diseases, including, but not limited to, various cancers, neurological diseases and cardiovascular diseases. The function of such regulatory RNAs is largely dependent on their subcellular localization. [...] Read more.
Circular RNAs (circRNAs) are regulatory RNAs which have recently been shown to have clinical significance in several diseases, including, but not limited to, various cancers, neurological diseases and cardiovascular diseases. The function of such regulatory RNAs is largely dependent on their subcellular localization. Several circRNAs have been shown to conduct antagonistic roles compared to the products of the linear isoforms, and thus need to be characterized distinctly from the linear RNAs. However, conventional fluorescent in situ hybridization (FISH) techniques cannot be employed directly to distinguish the signals from linear and circular isoforms because most circRNAs share the same sequence with the linear RNAs. In order to address this unmet need, we adapted the well-established method of single-molecule FISH by designing two sets of probes to differentiate the linear and circular RNA isoforms by virtue of signal colocalization. We call this method ‘circular fluorescent in situ hybridization’ (circFISH). Linear and circular RNAs were successfully visualized and quantified at a single-molecule resolution in fixed cells. RNase R treatment during the circFISH reduced the levels of linear RNAs while the circRNA levels remain unaltered. Furthermore, cells with shRNAs specific to circRNA showed the loss of circRNA levels, whereas the linear RNA levels were unaffected. The optimization of the in-situ RNase R treatment allowed the multiplexing of circFISH to combine it with organelle staining. CircFISH was found to be compatible with multiple sample types, including cultured cells and fresh-frozen and formalin-fixed tissue sections. Thus, we present circFISH as a versatile method for the simultaneous visualization and quantification of the distribution and localization of linear and circular RNA in fixed cells and tissue samples. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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14 pages, 854 KiB  
Article
The Analysis of Platelet-Derived circRNA Repertoire as Potential Diagnostic Biomarker for Non-Small Cell Lung Cancer
by Silvia D’Ambrosi, Allerdien Visser, Mafalda Antunes-Ferreira, Ankie Poutsma, Stavros Giannoukakos, Nik Sol, Siamack Sabrkhany, Idris Bahce, Marijke J. E. Kuijpers, Mirjam G. A. Oude Egbrink, Arjan W. Griffioen, Myron G. Best, Danijela Koppers-Lalic, Cees Oudejans and Thomas Würdinger
Cancers 2021, 13(18), 4644; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184644 - 16 Sep 2021
Cited by 25 | Viewed by 3880
Abstract
Tumor-educated Platelets (TEPs) have emerged as rich biosources of cancer-related RNA profiles in liquid biopsies applicable for cancer detection. Although human blood platelets have been found to be enriched in circular RNA (circRNA), no studies have investigated the potential of circRNA as platelet-derived [...] Read more.
Tumor-educated Platelets (TEPs) have emerged as rich biosources of cancer-related RNA profiles in liquid biopsies applicable for cancer detection. Although human blood platelets have been found to be enriched in circular RNA (circRNA), no studies have investigated the potential of circRNA as platelet-derived biomarkers for cancer. In this proof-of-concept study, we examine whether the circRNA signature of blood platelets can be used as a liquid biopsy biomarker for the detection of non-small cell lung cancer (NSCLC). We analyzed the total RNA, extracted from the platelet samples collected from NSCLC patients and asymptomatic individuals, using RNA sequencing (RNA-Seq). Identification and quantification of known and novel circRNAs were performed using the accurate CircRNA finder suite (ACFS), followed by the differential transcript expression analysis using a modified version of our thromboSeq software. Out of 4732 detected circRNAs, we identified 411 circRNAs that are significantly (p-value < 0.05) differentially expressed between asymptomatic individuals and NSCLC patients. Using the false discovery rate (FDR) of 0.05 as cutoff, we selected the nuclear receptor-interacting protein 1 (NRIP1) circRNA (circNRIP1) as a potential biomarker candidate for further validation by reverse transcription–quantitative PCR (RT-qPCR). This analysis was performed on an independent cohort of platelet samples. The RT-qPCR results confirmed the RNA-Seq data analysis, with significant downregulation of circNRIP1 in platelets derived from NSCLC patients. Our findings suggest that circRNAs found in blood platelets may hold diagnostic biomarkers potential for the detection of NSCLC using liquid biopsies. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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13 pages, 13912 KiB  
Article
GATCDA: Predicting circRNA-Disease Associations Based on Graph Attention Network
by Chen Bian, Xiu-Juan Lei and Fang-Xiang Wu
Cancers 2021, 13(11), 2595; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112595 - 25 May 2021
Cited by 23 | Viewed by 2747
Abstract
CircRNAs (circular RNAs) are a class of non-coding RNA molecules with a closed circular structure. CircRNAs are closely related to the occurrence and development of diseases. Due to the time-consuming nature of biological experiments, computational methods have become a better way to predict [...] Read more.
CircRNAs (circular RNAs) are a class of non-coding RNA molecules with a closed circular structure. CircRNAs are closely related to the occurrence and development of diseases. Due to the time-consuming nature of biological experiments, computational methods have become a better way to predict the interactions between circRNAs and diseases. In this study, we developed a novel computational method called GATCDA utilizing a graph attention network (GAT) to predict circRNA–disease associations with disease symptom similarity, network similarity, and information entropy similarity for both circRNAs and diseases. GAT learns representations for nodes on a graph by an attention mechanism, which assigns different weights to different nodes in a neighborhood. Considering that the circRNA–miRNA–mRNA axis plays an important role in the generation and development of diseases, circRNA–miRNA interactions and disease–mRNA interactions were adopted to construct features, in which mRNAs were related to 88% of miRNAs. As demonstrated by five-fold cross-validation, GATCDA yielded an AUC value of 0.9011. In addition, case studies showed that GATCDA can predict unknown circRNA–disease associations. In conclusion, GATCDA is a useful method for exploring associations between circRNAs and diseases. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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12 pages, 1848 KiB  
Article
A Novel Method to Predict Drug-Target Interactions Based on Large-Scale Graph Representation Learning
by Bo-Wei Zhao, Zhu-Hong You, Lun Hu, Zhen-Hao Guo, Lei Wang, Zhan-Heng Chen and Leon Wong
Cancers 2021, 13(9), 2111; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092111 - 27 Apr 2021
Cited by 26 | Viewed by 3081
Abstract
Identification of drug-target interactions (DTIs) is a significant step in the drug discovery or repositioning process. Compared with the time-consuming and labor-intensive in vivo experimental methods, the computational models can provide high-quality DTI candidates in an instant. In this study, we propose a [...] Read more.
Identification of drug-target interactions (DTIs) is a significant step in the drug discovery or repositioning process. Compared with the time-consuming and labor-intensive in vivo experimental methods, the computational models can provide high-quality DTI candidates in an instant. In this study, we propose a novel method called LGDTI to predict DTIs based on large-scale graph representation learning. LGDTI can capture the local and global structural information of the graph. Specifically, the first-order neighbor information of nodes can be aggregated by the graph convolutional network (GCN); on the other hand, the high-order neighbor information of nodes can be learned by the graph embedding method called DeepWalk. Finally, the two kinds of feature are fed into the random forest classifier to train and predict potential DTIs. The results show that our method obtained area under the receiver operating characteristic curve (AUROC) of 0.9455 and area under the precision-recall curve (AUPR) of 0.9491 under 5-fold cross-validation. Moreover, we compare the presented method with some existing state-of-the-art methods. These results imply that LGDTI can efficiently and robustly capture undiscovered DTIs. Moreover, the proposed model is expected to bring new inspiration and provide novel perspectives to relevant researchers. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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14 pages, 1763 KiB  
Article
Circular RNA in Chemonaive Lymph Node Negative Colon Cancer Patients
by Inge van den Berg, Marcel Smid, Robert R. J. Coebergh van den Braak, Carolien H. M. van Deurzen, Vanja de Weerd, John A. Foekens, Jan N. M. IJzermans, John W. M. Martens and Saskia M. Wilting
Cancers 2021, 13(8), 1903; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081903 - 15 Apr 2021
Cited by 2 | Viewed by 1730
Abstract
Circular RNAs (circRNAs) appear important in tumor progression of colon cancer (CC). We identified an extensive catalog of circRNAs in 181 chemonaive stage I/II colon tumors, who underwent curative surgery between 2007 and 2014. We identified circRNAs from RNAseq data, investigated common biology [...] Read more.
Circular RNAs (circRNAs) appear important in tumor progression of colon cancer (CC). We identified an extensive catalog of circRNAs in 181 chemonaive stage I/II colon tumors, who underwent curative surgery between 2007 and 2014. We identified circRNAs from RNAseq data, investigated common biology related to circRNA expression, and studied the association between circRNAs and relapse status, tumor stage, consensus molecular subtypes (CMS), tumor localization and microsatellite instability (MSI). We identified 2606 unique circRNAs. 277 circRNAs (derived from 260 genes) were repeatedly occurring in at least 20 patients of which 153 showed a poor or even negative (R < 0.3) correlation with the expression level of their linear gene. The circular junctions for circSATB2, circFGD6, circKMT2C and circPLEKHM3 were validated by Sanger sequencing. Multiple correspondence analysis showed that circRNAs were often co-expressed and that high diversity in circRNAs was associated with favorable disease-free survival (DFS), which was confirmed by Cox regression analysis (Hazard Ratio (HR) 0.60, 95% CI 0.38–0.97, p = 0.036). Considering individual circRNAs, absence of circMGA was significantly associated with relapse, whereas circSATB2, circNAB1, and circCEP192 were associated with both MSI and CMS. This study represents a showcase of the potential clinical utility of circRNAs for prognostic stratification in patients with stage I–II colon cancer and demonstrated that high diversity in circRNAs is associated with favorable DFS. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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Review

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16 pages, 1274 KiB  
Review
Circular RNA as a Novel Biomarker for Diagnosis and Prognosis and Potential Therapeutic Targets in Multiple Myeloma
by Alessandro Allegra, Nicola Cicero, Alessandro Tonacci, Caterina Musolino and Sebastiano Gangemi
Cancers 2022, 14(7), 1700; https://doi.org/10.3390/cancers14071700 - 27 Mar 2022
Cited by 20 | Viewed by 2666
Abstract
Circular RNAs (circRNAs) are a novel type of covalently closed RNAs involved in several physiological and pathological processes. They display tissue-specific expression and are constant, abundant, and highly conserved, making them perfect markers for diagnosis and prognosis. Several studies have proposed that circRNAs [...] Read more.
Circular RNAs (circRNAs) are a novel type of covalently closed RNAs involved in several physiological and pathological processes. They display tissue-specific expression and are constant, abundant, and highly conserved, making them perfect markers for diagnosis and prognosis. Several studies have proposed that circRNAs are also differentially produced in malignancies where they have oncogenic effects. Furthermore, circRNAs affecting microRNAs modify the expression profile of several transcription factors which play essential roles in tumors. CircRNAs within the hematopoietic compartment were identified as modulators of mechanisms able to enhance or suppress tumor progression in blood malignancies. Moreover, several circRNAs were suggested to confer resistance to the conventional drugs employed in hematopoietic cancers. In this review, we highlight the growing role and the controlling mechanisms by which circRNAs modify multiple myeloma genesis. We propose that circRNAs can be considered as potential diagnostic and prognostic markers, can induce chemoresistance, and might represent novel therapeutic targets for multiple myeloma. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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19 pages, 29862 KiB  
Review
Circular RNAs Modulate Cancer Hallmark and Molecular Pathways to Support Cancer Progression and Metastasis
by Aliaksandr A. Yarmishyn, Afeez Adekunle Ishola, Chieh-Yu Chen, Nalini Devi Verusingam, Vimalan Rengganaten, Habeebat Aderonke Mustapha, Hao-Kai Chuang, Yuan-Chi Teng, Van Long Phung , Po-Kuei Hsu, Wen-Chang Lin, Hsin-I Ma, Shih-Hwa Chiou and Mong-Lien Wang
Cancers 2022, 14(4), 862; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14040862 - 09 Feb 2022
Cited by 11 | Viewed by 2628
Abstract
Circular RNAs (circRNAs) are noncoding products of backsplicing of pre-mRNAs which have been established to possess potent biological functions. Dysregulated circRNA expression has been linked to diseases including different types of cancer. Cancer progression is known to result from the dysregulation of several [...] Read more.
Circular RNAs (circRNAs) are noncoding products of backsplicing of pre-mRNAs which have been established to possess potent biological functions. Dysregulated circRNA expression has been linked to diseases including different types of cancer. Cancer progression is known to result from the dysregulation of several molecular mechanisms responsible for the maintenance of cellular and tissue homeostasis. The dysregulation of these processes is defined as cancer hallmarks, and the molecular pathways implicated in them are regarded as the targets of therapeutic interference. In this review, we summarize the literature on the investigation of circRNAs implicated in cancer hallmark molecular signaling. First, we present general information on the properties of circRNAs, such as their biogenesis and degradation mechanisms, as well as their basic molecular functions. Subsequently, we summarize the roles of circRNAs in the framework of each cancer hallmark and finally discuss the potential as therapeutic targets. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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18 pages, 3317 KiB  
Review
The Role of Circular RNAs in DNA Damage Response and Repair
by Angelos Papaspyropoulos, Orsalia Hazapis, Nefeli Lagopati, Aikaterini Polyzou, Anastasios D. Papanastasiou, Michalis Liontos, Vassilis G. Gorgoulis and Athanassios Kotsinas
Cancers 2021, 13(21), 5352; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215352 - 26 Oct 2021
Cited by 9 | Viewed by 2094
Abstract
Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been [...] Read more.
Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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22 pages, 1031 KiB  
Review
The Emerging Functions of Circular RNAs in Bladder Cancer
by Kai Sun, Di Wang, Burton B. Yang and Jian Ma
Cancers 2021, 13(18), 4618; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184618 - 15 Sep 2021
Cited by 9 | Viewed by 2062
Abstract
Bladder cancer (BC) is among the top ten most common cancer types worldwide and is a serious threat to human health. Circular RNAs (circRNAs) are a new class of non-coding RNAs generated by covalently closed loops through back-splicing. As an emerging research hotspot, [...] Read more.
Bladder cancer (BC) is among the top ten most common cancer types worldwide and is a serious threat to human health. Circular RNAs (circRNAs) are a new class of non-coding RNAs generated by covalently closed loops through back-splicing. As an emerging research hotspot, circRNAs have attracted considerable attention due to their high conservation, stability, abundance, and specificity of tissue development. Accumulating evidence has revealed different form of circRNAs are closely related to the malignant phenotype, prognosis and chemotherapy resistance of BC, suggesting that different circRNAs may be promising biomarkers and have therapeutic significance in BC. The intention of this review is to summarize the mechanisms of circRNA-mediated BC progression and their diagnostic and prognostic value as biomarkers, as well as to further explore their roles in chemotherapy resistance. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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17 pages, 921 KiB  
Review
The Role of Circular RNAs in Keratinocyte Carcinomas
by Thomas Meyer, Michael Sand, Lutz Schmitz and Eggert Stockfleth
Cancers 2021, 13(16), 4240; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164240 - 23 Aug 2021
Cited by 3 | Viewed by 2246
Abstract
Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in [...] Read more.
Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in BCC belong to the sonic hedgehog pathway, whereas, in cSCC, TP53, CDKN2A, NOTCH1/2 and others are most frequently mutated. In addition, the dysregulation of factors associated with epithelial to mesenchymal transition (EMT) was shown in invasive cSCC. The expression of factors associated with tumorigenesis can be controlled in several ways and include non-coding RNA molecules, such as micro RNAs (miRNA) long noncoding RNAs (lncRNA) and circular RNAs (circRNA). To update findings on circRNA in KC, we reviewed 13 papers published since 2016, identified in a PubMed search. In both BCC and cSCC, numerous circRNAs were identified that were differently expressed compared to healthy skin. Some of them were shown to target miRNAs that are also dysregulated in KC. Moreover, some studies confirmed the biological functions of individual circRNAs involved in cancer development. Thus, circRNAs may be used as biomarkers of disease and disease progression and represent potential targets of new therapeutic approaches for KC. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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13 pages, 918 KiB  
Review
Mechanisms Regulating Abnormal Circular RNA Biogenesis in Cancer
by Ying Huang and Qubo Zhu
Cancers 2021, 13(16), 4185; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164185 - 20 Aug 2021
Cited by 31 | Viewed by 2435
Abstract
Circular RNAs (circRNAs), which are a class of endogenous RNA with covalently closed loops, play important roles in epigenetic regulation of gene expression at both the transcriptional and post-transcriptional level. Accumulating evidence demonstrated that numerous circRNAs were abnormally expressed in tumors and their [...] Read more.
Circular RNAs (circRNAs), which are a class of endogenous RNA with covalently closed loops, play important roles in epigenetic regulation of gene expression at both the transcriptional and post-transcriptional level. Accumulating evidence demonstrated that numerous circRNAs were abnormally expressed in tumors and their dysregulation was involved in the tumorigenesis and metastasis of cancer. Although the functional mechanisms of many circRNAs have been revealed, how circRNAs are dysregulated in cancer remains elusive. CircRNAs are generated by a “back-splicing” process, which is regulated by different cis-regulatory elements and trans-acting proteins. Therefore, how these cis and trans elements change during tumorigenesis and how they regulate the biogenesis of circRNAs in cancer are two questions that interest us. In this review, we summarized the pathways for the biogenesis of circRNAs; and then illustrated how circRNAs dysregulated in cancer by discussing the changes of cis-regulatory elements and trans-acting proteins that related to circRNA splicing and maturation in cancer. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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13 pages, 1218 KiB  
Review
Insights into the Evolving Roles of Circular RNAs in Cancer
by Katherine Louise Harper, Timothy James Mottram and Adrian Whitehouse
Cancers 2021, 13(16), 4180; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164180 - 20 Aug 2021
Cited by 16 | Viewed by 2219
Abstract
The majority of RNAs transcribed from the human genome have no coding capacity and are termed non-coding RNAs (ncRNAs). It is now widely accepted that ncRNAs play key roles in cell regulation and disease. Circular RNAs (circRNAs) are a form of ncRNA, characterised [...] Read more.
The majority of RNAs transcribed from the human genome have no coding capacity and are termed non-coding RNAs (ncRNAs). It is now widely accepted that ncRNAs play key roles in cell regulation and disease. Circular RNAs (circRNAs) are a form of ncRNA, characterised by a closed loop structure with roles as competing endogenous RNAs (ceRNAs), protein interactors and transcriptional regulators. Functioning as key cellular regulators, dysregulated circRNAs have a significant impact on disease progression, particularly in cancer. Evidence is emerging of specific circRNAs having oncogenic or tumour suppressive properties. The multifaceted nature of circRNA function may additionally have merit as a novel therapeutic target, either in treatment or as a novel biomarker, due to their cell-and disease-state specific expression and long-term stability. This review aims to summarise current findings on how circRNAs are dysregulated in cancer, the effects this has on disease progression, and how circRNAs may be targeted or utilised as future potential therapeutic options. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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30 pages, 4969 KiB  
Review
Circular RNAs: Emerging Regulators of the Major Signaling Pathways Involved in Cancer Progression
by Maria Papatsirou, Pinelopi I. Artemaki, Paraskevi Karousi, Andreas Scorilas and Christos K. Kontos
Cancers 2021, 13(11), 2744; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112744 - 01 Jun 2021
Cited by 43 | Viewed by 3862
Abstract
Signal transduction is an essential process that regulates and coordinates fundamental cellular processes, such as development, immunity, energy metabolism, and apoptosis. Through signaling, cells are capable of perceiving their environment and adjusting to changes, and most signaling cascades ultimately lead to alterations in [...] Read more.
Signal transduction is an essential process that regulates and coordinates fundamental cellular processes, such as development, immunity, energy metabolism, and apoptosis. Through signaling, cells are capable of perceiving their environment and adjusting to changes, and most signaling cascades ultimately lead to alterations in gene expression. Circular RNAs (circRNAs) constitute an emerging type of endogenous transcripts with regulatory roles and unique properties. They are stable and expressed in a tissue-, cell-, and developmental stage-specific manner, while they are involved in the pathogenesis of several diseases, including cancer. Aberrantly expressed circRNAs can mediate cancer progression through regulation of the activity of major signaling cascades, such as the VEGF, WNT/β-catenin, MAPK, PI3K/AKT, and Notch signaling pathways, as well as by interfering with signaling crosstalk. Deregulated signaling can then function to induce angiogenesis, promote invasion, migration, and metastasis, and, generally, modulate the hallmarks of cancer. In this review article, we summarize the most recently described and intriguing cases of circRNA-mediated signaling regulation that are involved in cancer progression, and discuss the biomarker potential of circRNAs, as well as future therapeutic applications. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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Other

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19 pages, 4113 KiB  
Hypothesis
hsa_circ_0001275 Is One of a Number of circRNAs Dysregulated in Enzalutamide Resistant Prostate Cancer and Confers Enzalutamide Resistance In Vitro
by Marvin C. J. Lim, Anne-Marie Baird, John Greene, Ciara McNevin, Karine Ronan, Petar Podlesniy, Orla Sheils, Steven G. Gray, Ray S. McDermott and Stephen P. Finn
Cancers 2021, 13(24), 6383; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246383 - 20 Dec 2021
Cited by 3 | Viewed by 2745
Abstract
Background: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including [...] Read more.
Background: Enzalutamide is part of the treatment regimen for metastatic castration-resistant prostate cancer (MCRPC). However, both intrinsic and acquired resistance to the drug remain substantial clinical quandaries. circRNAs, a novel type of non-coding RNA, have been identified in a number of cancers including prostate cancer and have been associated with cancer development and progression. circRNAs have shown great potential as clinically useful blood-based ‘liquid biopsies’ and as therapeutic targets in prostate cancer. The aim of this study was to examine the role of circRNA transcripts in enzalutamide-resistant prostate cancer cells and assess their utility as biomarkers. Methods: An isogenic cell line model of enzalutamide resistance was subjected to circRNA microarray profiling. Several differentially expressed circRNAs, along with their putative parental genes were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). circRNAs of interest were stably overexpressed in the control cell line and drug sensitivity was assessed using an ELISA-based proliferation assay. The candidate circRNA, hsa_circ_0001275, was measured in patient plasma samples using RT-droplet digital PCR (RT-ddPCR). Results: hsa_circ_0001275 and its parental gene, PLCL2, were significantly up-regulated in strongly resistant clones vs. control (p < 0.05). Overexpression of hsa_circ_0001275 in the control cell line resulted in increased resistance to enzalutamide (p < 0.05). While RT-ddPCR analysis of hsa_circ_0001275 expression in plasma samples of 44 clinical trial participants showed a trend that mirrored the stages of disease activity (as defined by PSA level), the association did not reach statistical significance. Conclusions: Our data suggest that increased levels of hsa_circ_0001275 contribute to enzalutamide resistance. hsa_circ_0001275 plasma expression showed a trend that mirrors the PSA level at specific disease time points, indicating that circRNAs mirror disease recurrence and burden and may be associated with enzalutamide resistance. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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