Circular RNA as a Potential Biomarker for Melanoma: A Systematic Review

Circular RNAs (circRNAs) are newly discovered RNAs with covalently looped structures. Due to their resistance to RNAase degradation and tissue-specific expression, circRNAs are expected to be potential biomarkers in early diagnosis and target treatment of many diseases. However, the role of circRNAs in melanoma still needs to be systematically reviewed for better understanding and further research. Based on published articles in PubMed, Embase, Cochrane Library, and Web of Science database, we systematically reviewed the implications and recent advances of circRNAs in melanoma, focusing on function, mechanism, and correlation with melanoma progression. According to inclusion and exclusion criteria, a total of 19 articles were finally included in this systematic review. Of the 19 studies, 17 used human samples, including melanoma tissues (n = 16) and blood serum of patients with melanoma (n = 1). The sample size of the study group ranged from 20 to 105 based on the reported data. Several studies explored the association between circRNAs and clinicopathological characteristics. circRNA dysregulation was commonly observed in melanoma patients. circRNAs function in melanoma by miRNA sponging and interaction with RNA binding proteins (RBP), ultimately controlling several important signaling pathways and cancer-related cellular processes, including proliferation, migration, invasion, metastasis, apoptosis, and glucose metabolism. circRNA expression could be associated with prognostic factors and drug responses, consolidating the potential clinical value in melanoma. Herein, we clarified the functional, prognostic, and predictive roles of circRNAs in melanoma in this systematic review, providing future directions for studies on melanoma-associated circRNAs.

Download Full-text

Circular RNA and its mechanisms in diabetic retinopathy: a systematic review

10.1101/2020.02.07.20021204 ◽

2020 ◽

Author(s):

Miao He ◽

Rouxi Zhou ◽

Sen Liu ◽

Weijing Cheng ◽

Wei Wang

Keyword(s):

Systematic Review ◽

Diabetic Retinopathy ◽

Rna Binding ◽

Rna Binding Proteins ◽

Protein Complexes ◽

Protein Translation ◽

Circular Rna ◽

Circular Rnas ◽

Eye Tissues ◽

Rna Protein Complexes

ABSTRACTCircular RNAs (CircRNAs) are endogenous long non-coding RNAs. Unlike linear RNAs, they are structurally continuous and covalently closed, without 5 ’caps or 3’ polyadenylation tails. High-throughput RNA sequencing has enabled people to find several endogenous circRNAs in different species and tissues. circRNA mainly acts as a sponge for microRNAs in cytoplasm to regulates protein translation, or interacts with RNA-binding proteins to generate RNA protein complexes that control transcription. circRNAs are closely associated with diseases such as diabetes, neurological disorders, cardiovascular diseases and cancer, which indicates that circRNAs are closely related to and also play an important functional role in the occurrence and development of human diseases. Recent studies have shown that they are differentially expressed in healthy and diseased eye tissues. There lacks of biomarkers for early detection of diabetic retinopathy, and the newly discovered circRNAs seem to be an ideal candidate of novel molecular markers and therapeutic targets. However, the molecular mechanism of circRNAs activity in the occurrence and development of diabetic retinopathy are not clear yet. This systematic review aims to summarize the research status on function and mechanism of circRNAs in regulating the occurrence of diabetic retinopathy.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms22147477 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7477

Author(s):

Rok Razpotnik ◽

Petra Nassib ◽

Tanja Kunej ◽

Damjana Rozman ◽

Tadeja Režen

Keyword(s):

Hepatocellular Carcinoma ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulatory Protein ◽

Circular Rna ◽

Differentially Expressed ◽

Circular Rnas ◽

Bioinformatics Analyses ◽

Published Evidence

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

Download Full-text

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.

Download Full-text

Systematic Review and Meta-Analysis of the Utility of Circular RNAs as Biomarkers of Hepatocellular Carcinoma

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2019/1684039 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Qingqin Hao ◽

Yadi Han ◽

Wei Xia ◽

Qinghui Wang ◽

Huizhong Qian

Keyword(s):

Likelihood Ratio ◽

Meta Analysis ◽

Positive Likelihood Ratio ◽

Negative Likelihood Ratio ◽

Diagnostic Odds Ratio ◽

Clinicopathological Characteristics ◽

Cochrane Library ◽

Circular Rnas ◽

Clinical Value ◽

Sensitivity Specificity

Emerging studies have reported circRNAs were dysregulated in HCC. However, the clinical value of these circRNAs remains to be clarified. Herein, we aimed to comprehensively explore their association with the diagnosis, prognosis, and clinicopathological characteristics of HCC. PubMed, EMBASE, Web of Science, and Cochrane Library databases were comprehensively searched for eligible studies up to October 30, 2018. The diagnostic effect was evaluated by the pooled sensitivity, specificity, and other indexes. The pooled hazard ratio (HR) for overall survival (OS) and recurrence free survival (RFS) was calculated to assess the prognostic value. Ten studies on diagnosis, 12 on prognosis, and 23 on clinicopathology were identified from the databases. A total of 11 upregulated and 11 downregulated circRNAs showed an association with clinicopathological features of HCC. For the diagnosis analyses, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of circRNAs for HCC were 0.74 (95%CI: 0.65-0.82) and 0.76 (95%CI: 0.70-0.81), 3.1 (95%CI: 2.5-3.8), 0.34 (95%CI: 0.25-0.47), and 9 (95%CI: 6-14), respectively. The area under SROC curve (AUC) was 0.81 (95% CI: 0.78–0.84), indicating moderate diagnostic accuracy. In stratified analyses, the diagnostic performance of circRNAs varied based on the source of control and specimen type. For the prognosis analyses, increased expression of upregulated circRNAs was associated with worse OS (HR: 3.67, 95%: 2.07-6.48), while high expression of downregulated circRNAs was associated with better OS (HR: 0.38, 95%: 0.30-0.48). In conclusion, this study reveals that circRNAs may serve as promising diagnostic and prognostic biomarkers for HCC. However, further investigations are still required to explore the clinical value of circRNAs.

Download Full-text

Prognostic Value of Circular RNA ciRS-7 in Various Cancers: A PRISMA-Compliant Meta-Analysis

BioMed Research International ◽

10.1155/2020/1487609 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Guangwei Tian ◽

Guang Li ◽

Lin Guan ◽

Zihui Wang ◽

Nan Li

Keyword(s):

Meta Analysis ◽

Prognostic Indicator ◽

Tumor Stage ◽

Circular Rna ◽

Cochrane Library ◽

Size Analysis ◽

Circular Rnas ◽

Hazard Ratios ◽

Potential Biomarker ◽

The Cochrane Library

Background. Circular RNAs (circRNAs) have been shown to be involved in tumorigenesis. As a member of circRNAs, ciRS-7 is thought to be a negative prognostic indicator in multiple types of cancer. The present study aimed to comprehensively explore the value of ciRS-7 in tumor malignancy. Materials and Methods. A systematic review of PubMed, Web of Science, and the Cochrane library was carried out to examine the related studies. The pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated from the available publications by STATA 12.0. Subgroup analysis, publication bias, sensitivity analysis, and meta-regression were conducted. Results. This meta-analysis included 1,714 patients from 13 cohorts. The results suggested that high ciRS-7 expression was significantly associated with overall survival (OS) (HR = 2.17, 95% CI = 1.50–3.15, P<0.001) in various cancers. Stratified analyses indicated that elevated levels of ciRS-7 appeared to be a powerful prognostic biomarker for patients with non-small-cell lung cancer (NSCLC) (HR: 2.50, 95% CI: 1.07–6.07, P=0.035), colorectal cancer (CRC) (HR: 1.95, 95% CI: 1.34–2.84, P<0.001), and gastric cancer (GC) (HR: 2.32, 95% CI: 1.48–3.64, P<0.001). A similar effect was also observed in subgroup of sample size, analysis method, and cutoff value, except for ethnicity. The increased ciRS-7 expression was associated with a higher tumor stage (OR = 2.30, 95% CI: 1.69–3.13, P<0.001). Conclusions. High expression of ciRS-7 has a significant correlation with the high stage in various cancers, and ciRS-7 is intimately associated with an adverse OS in numerous cancers. Thus, ciRS-7 may act as a potential biomarker for the development of malignancies.

Download Full-text

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.

Download Full-text

Biogenesis mechanisms of circular RNA can be categorized through feature extraction of a machine learning model

Bioinformatics ◽

10.1093/bioinformatics/btz705 ◽

2019 ◽

Vol 35 (23) ◽

pp. 4867-4870

Author(s):

Chengyu Liu ◽

Yu-Chen Liu ◽

Hsien-Da Huang ◽

Wei Wang

Keyword(s):

Feature Extraction ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cpg Island ◽

Cpg Islands ◽

Circular Rna ◽

Training Data ◽

Supplementary Information ◽

Circular Rnas ◽

Genomic Locus

Abstract Motivation In recent years, multiple circular RNAs (circRNA) biogenesis mechanisms have been discovered. Although each reported mechanism has been experimentally verified in different circRNAs, no single biogenesis mechanism has been proposed that can universally explain the biogenesis of all tens of thousands of discovered circRNAs. Under the hypothesis that human circRNAs can be categorized according to different biogenesis mechanisms, we designed a contextual regression model trained to predict the formation of circular RNA from a random genomic locus on human genome, with potential biogenesis factors of circular RNA as the features of the training data. Results After achieving high prediction accuracy, we found through the feature extraction technique that the examined human circRNAs can be categorized into seven subgroups, according to the presence of the following sequence features: RNA editing sites, simple repeat sequences, self-chains, RNA binding protein binding sites and CpG islands within the flanking regions of the circular RNA back-spliced junction sites. These results support all of the previously reported biogenesis mechanisms of circRNA and solidify the idea that multiple biogenesis mechanisms co-exist for different subset of human circRNAs. Furthermore, we uncover a potential new links between circRNA biogenesis and flanking CpG island. We have also identified RNA binding proteins putatively correlated with circRNA biogenesis. Availability and implementation Scripts and tutorial are available at http://wanglab.ucsd.edu/star/circRNA. This program is under GNU General Public License v3.0. Supplementary information Supplementary data are available at Bioinformatics online.

Download Full-text

An autoregulation loop in fust-1 for circular RNA regulation in Caenorhabditis elegans

10.1101/2021.03.22.436400 ◽

2021 ◽

Author(s):

Dong Cao

Keyword(s):

Caenorhabditis Elegans ◽

Rna Binding ◽

Rna Binding Proteins ◽

Exon Skipping ◽

Circular Rna ◽

Circular Rnas ◽

Rna Regulation ◽

Fused In Sarcoma ◽

Specific Factors ◽

Isoform B

Circular RNAs (circRNAs) are always expressed tissue-specifically, suggestive of specific factors that regulate their biogenesis. Here, taking advantage of available mutation strains of RNA binding proteins (RBPs) in Caenorhabditis elegans, I performed a screening of circRNA regulation in thirteen conserved RBPs. Among them, loss of FUST-1, the homolog of FUS (Fused in Sarcoma), caused downregulation of multiple circRNAs. By rescue experiments, I confirmed FUST-1 as a circRNA regulator. Further, I showed that FUST-1 regulates circRNA formation without affecting the levels of the cognate linear mRNAs. When recognizing circRNA pre-mRNAs, FUST-1 can affect both exon-skipping and circRNA in the same genes. Moreover, I identified an autoregulation loop in fust-1, where FUST-1, isoform a promotes the skipping of exon 5 of its own pre-mRNA, which produces FUST-1, isoform b with different N-terminal sequences. FUST-1, isoform a is the functional isoform in circRNA regulation. Although FUST-1, isoform b has the same functional domains as isoform a, it cannot regulate either exon-skipping or circRNA formation.

Download Full-text

Novel insights toward human stroke-related epigenetics: circular RNA and its impact in poststroke processes

Epigenomics ◽

10.2217/epi-2020-0128 ◽

2020 ◽

Vol 12 (22) ◽

pp. 1957-1968

Author(s):

Pablo W Silva ◽

Samara M M Shimon ◽

Leonardo M de Brito ◽

Laís Reis-das-Mercês ◽

Leandro Magalhães ◽

...

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Circular Rna ◽

Functional Enrichment ◽

Circular Rnas ◽

Global Expression Profile ◽

Human Stroke ◽

Target Rna

Aim: Circular RNAs (circRNAs) are dysregulated in complex diseases, so we investigated their global expression profile in stroke. Material & methods: Public RNA-Seq data of human ischemic stroke lesion tissues and controls were used to perform the global expression analysis. Target RNA binding proteins and microRNAs were predicted in silico. Functional enrichment analysis was performed to infer the circRNAs’ potential roles. Results: We found that circRNAs are potentially involved in synaptic components and transmission, inflammation and ataxia. An integrative analysis revealed that hsa_circ_0078299 and FXN may be major players in the molecular stroke-context. Conclusion: Our results suggest a broad involvement of circRNAs in some stroke-related processes, indicating their potential as therapeutic targets to allow neuroprotection and brain recovery.

Download Full-text

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.

Download Full-text