Circular RNAs: a new class of biomarkers as a rising interest in laboratory medicine

Abstract Circular RNAs (circRNAs) are a distinct family of RNAs derived from the non-regular process of alternative splicing. CircRNAs have recently gained interest in transcriptome research due to their potential regulatory functions during gene expression. CircRNAs can act as microRNA sponges and affect transcription through their complex involvement in regular transcriptional processes. Some early studies also suggested significant roles for circRNAs in human diseases, especially cancer, as biomarkers and potential clinical targets. Therefore, there is a great need for laboratory scientists to translate these findings into clinical tools to advance testing for human diseases. To facilitate a better understanding of the promise of circRNAs, we focus this review on selected basic aspects of circRNA research, specifically biogenesis, function, analytical issues regarding identification and validation and examples of expression data in relation to human diseases. We further emphasize the unique challenges facing laboratory medicine with regard to circRNA research, particularly in the development of robust assays for circRNA detection in different body fluids and the need to collaborate with clinicians in the design of clinical studies.

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Advances in the Identification of Circular RNAs and Research Into circRNAs in Human Diseases

Frontiers in Genetics ◽

10.3389/fgene.2021.665233 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shihu Jiao ◽

Song Wu ◽

Shan Huang ◽

Mingyang Liu ◽

Bo Gao

Keyword(s):

Neurological Disorders ◽

Closed Loop ◽

Significant Proportion ◽

Human Diseases ◽

Circular Rnas ◽

The Status ◽

Research Questions ◽

Non Coding Rnas ◽

Microrna Sponges

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) with a closed-loop structure that are mainly produced by variable processing of precursor mRNAs (pre-mRNAs). They are widely present in all eukaryotes and are very stable. Currently, circRNA studies have become a hotspot in RNA research. It has been reported that circRNAs constitute a significant proportion of transcript expression, and some are significantly more abundantly expressed than other transcripts. CircRNAs have regulatory roles in gene expression and critical biological functions in the development of organisms, such as acting as microRNA sponges or as endogenous RNAs and biomarkers. As such, they may have useful functions in the diagnosis and treatment of diseases. CircRNAs have been found to play an important role in the development of several diseases, including atherosclerosis, neurological disorders, diabetes, and cancer. In this paper, we review the status of circRNA research, describe circRNA-related databases and the identification of circRNAs, discuss the role of circRNAs in human diseases such as colon cancer, atherosclerosis, and gastric cancer, and identify remaining research questions related to circRNAs.

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BBCancer: an expression atlas of blood-based biomarkers in the early diagnosis of cancers

Nucleic Acids Research ◽

10.1093/nar/gkz942 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zhixiang Zuo ◽

Huanjing Hu ◽

Qingxian Xu ◽

Xiaotong Luo ◽

Di Peng ◽

...

Keyword(s):

Gene Expression ◽

Early Detection ◽

Cancer Patients ◽

High Throughput ◽

Early Detection Of Cancer ◽

Circular Rnas ◽

Expression Data ◽

Blood Samples ◽

Cancer Types ◽

High Throughput Gene Expression

Abstract The early detection of cancer holds the key to combat and control the increasing global burden of cancer morbidity and mortality. Blood-based screenings using circulating DNAs (ctDNAs), circulating RNA (ctRNAs), circulating tumor cells (CTCs) and extracellular vesicles (EVs) have shown promising prospects in the early detection of cancer. Recent high-throughput gene expression profiling of blood samples from cancer patients has provided a valuable resource for developing new biomarkers for the early detection of cancer. However, a well-organized online repository for these blood-based high-throughput gene expression data is still not available. Here, we present BBCancer (http://bbcancer.renlab.org/), a web-accessible and comprehensive open resource for providing the expression landscape of six types of RNAs, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), tRNA-derived fragments (tRFRNAs) and Piwi-interacting RNAs (piRNAs) in blood samples, including plasma, CTCs and EVs, from cancer patients with various cancer types. Currently, BBCancer contains expression data of the six RNA types from 5040 normal and tumor blood samples across 15 cancer types. We believe this database will serve as a powerful platform for developing blood biomarkers.

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The emerging role of circular RNAs in breast cancer

Bioscience Reports ◽

10.1042/bsr20190621 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 7

Author(s):

Si-ying Zhou ◽

Wei Chen ◽

Su-jin Yang ◽

Zi-han Xu ◽

Jia-hua Hu ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Invasion ◽

Clinical Characteristics ◽

Circular Rnas ◽

Rnase R ◽

New Class ◽

Regulatory Rnas ◽

And Function

AbstractBreast cancer (BCa) is one of the most frequently diagnosed cancers and leading cause of cancer deaths among females worldwide. Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by circular shape resulting from covalently closed continuous loops that are capable of regulating gene expression at transcription or post-transcription levels. With the unique structures, circRNAs are resistant to exonuclease RNase R and maintain stability more easily than linear RNAs. Recently, an increasing number of circRNAs are discovered and reported to show different expression in BCa and these dysregulated circRNAs were correlated with patients’ clinical characteristics and grade in the progression of BCa. CircRNAs participate in the bioprocesses of carcinogenesis of BCa, including cell proliferation, apoptosis, cell cycle, tumorigenesis, vascularization, cell invasion, migration as well as metastasis. Here we concentrated on biogenesis and function of circRNAs, summarized their implications in BCa and discussed their potential as diagnostic and therapeutic targets for BCa.

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CircRNAs as potent biomarkers in ovarian cancer: a systematic scoping review

Cellular & Molecular Biology Letters ◽

10.1186/s11658-021-00284-7 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Zahra Foruzandeh ◽

Fatemeh Zeinali-Sehrig ◽

Kazem Nejati ◽

Dara Rahmanpour ◽

Fariba Pashazadeh ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Chemotherapy Resistance ◽

Developed Countries ◽

Diagnostic Tools ◽

Circular Rnas ◽

Regulate Gene Expression ◽

Microrna Sponges ◽

Insight Into ◽

Regulate Gene

AbstractMore powerful prognostic and diagnostic tools are urgently needed for identifying and treating ovarian cancer (OC), which is the most fatal malignancy in women in developed countries. Circular RNAs (circRNAs) are conservative and stable looped molecules that can regulate gene expression by competing with other endogenous microRNA sponges. This discovery provided new insight into novel methods for regulating genes that are involved in many disorders and cancers. This review focuses on the dysregulated expression of circRNAs as well as their diagnostic and prognostic values in OC. We found that studies have identified twenty-one downregulated circRNAs and fifty-seven upregulated ones. The results of these studies confirm that circRNAs might be potent biomarkers with diagnostic, prognostic and therapeutic target value for OC. We also consider the connection between circRNAs and OC cell proliferation, apoptosis, metastasis, and chemotherapy resistance and sensitivity.

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NCMP-04. BRAIN-UMAP: THE GENETIC INTERSECTION BETWEEN NEUROSCIENCE, NEUROLOGY, PSYCHIATRY, AND ONCOLOGY

Neuro-Oncology ◽

10.1093/neuonc/noab196.577 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi148-vi148

Author(s):

Sonali Arora ◽

Nicholas Nuechterlein ◽

Siobhan Pattwell ◽

Eric Holland

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Brain Regions ◽

Human Diseases ◽

Next Generation Sequencing Data ◽

Normal Brain ◽

Expression Data ◽

Sequencing Data ◽

Insight Into ◽

Genome Atlas

Abstract Whole transcriptome sequencing (RNA-seq) is an important tool for understanding genetic mechanisms underlying human diseases and gaining a better insight into complex human diseases. Several ground-breaking projects have uniformly processed RNASeq data from publicly available studies to enable cross-comparison. One noteworthy study is the recount2 pipeline, which in 2017, has reprocessed ~70,0000 samples from Short Read Archive(SRA), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx). This vast dataset also includes gene expression data for GTEx-defined brain regions, neurological and psychiatric disorders (such as Parkinson's, Alzheimer’s, Huntington’s) and gliomas (such as TCGA, Chinese Glioma Genome Atlas (CGGA)). We apply uniform manifold approximation and projection (UMAP), a non-linear dimension reduction tool, to bulk gene expression data from brain-related diseases to build a BRAIN-UMAP, which allows for visualization of gene expression profiles across datasets. This UMAP shows that while gliomas form a distinct cluster, the neurological and psychiatric diseases are similar to GTEX-defined normal brain regions which exhibit tissue-specific profiles and patterns. Incorporating gliomas from various publicly available datasets also allows for the ability to observe unique clustering of particular subtypes, which can increase our genetic understanding of the disease. We also present a resource where researchers interested in mechanisms, can easily compare, and contrast the expression of a given gene and/or pathway of interest across various diseases, gliomas, and normal brain regions. Our current study, focusing on brain related diseases, offers insight into what may be possible for the broader neuroscientific community if we continually reprocess newly available brain related RNASeq samples using recount2. Additionally, if we build similar uniformly processing pipelines for other kinds of next-generation sequencing data, we would be able to use multi-omic sequencing data to find novel associations between biological entities and increase our mechanistic knowledge of the disease.

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Comparative hepatic gene expression profiling of rats treated with 1H,1H,2H,2H-heptadecafluorodecan-1-ol or with pentadecafluorooctanoic acid

Physiological Genomics ◽

10.1152/physiolgenomics.00225.2007 ◽

2008 ◽

Vol 34 (3) ◽

pp. 285-303 ◽

Cited By ~ 8

Author(s):

Anja Julie Nilsen ◽

Maria A. Landin ◽

Kristin H. Haug ◽

Frode Fonnum ◽

Urs Berger ◽

...

Keyword(s):

Gene Expression ◽

Radical Scavenging ◽

Bioinformatic Analysis ◽

Progressive Increase ◽

Peroxisome Proliferator ◽

Hepatic Gene Expression ◽

Expression Data ◽

Rt Pcr ◽

Pathways Analysis ◽

Regulatory Functions

Pentadecafluorooctanoic acid is an established peroxisome proliferator. Little is known about effects of treatment with 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol, which is metabolized to pentadecafluorooctanoic acid. We compared effects of various dosages (3, 10, or 25 mg/kg body wt) of each of these compounds on hepatic gene expression in rats with microarrays. Microarray data were validated by real-time RT-PCR. Expression data were also correlated with hepatic activities of selected enzymes and with hepatic levels of pentadecafluorooctanoic acid and 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol. Pentadecafluorooctanoic acid caused the more powerful change in gene expression, in terms of both number of genes affected and extent of change in expression. Across the dosages used pentadecafluorooctanoic acid and 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol caused significant ( P ≤ 0.05) changes in expression for 441 and 105 genes, respectively. With 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol ∼38% of the 105 genes exhibited decreased expression with a dose of 25 mg/kg body wt, these genes also appearing less responsive to treatment at the lower dosages. Bioinformatic analysis suggested that these genes are associated with regulatory functions. With pentadecafluorooctanoic acid, increasing dosage up to 10 mg/kg body wt brought about progressive increase in expression of affected genes. Pathways analysis suggested similar effects of the two compounds on lipid and amino acid metabolism. Marked differences were also found, particularly with respect to effects on genes related to oxidative phosphorylation, oxidative metabolism, free radical scavenging, xenobiotic metabolism, and complement and coagulation cascades.

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Identifying splits with clear separation: a new class discovery method for gene expression data

Bioinformatics ◽

10.1093/bioinformatics/17.suppl_1.s107 ◽

2001 ◽

Vol 17 (Suppl 1) ◽

pp. S107-S114 ◽

Cited By ~ 27

Author(s):

A. von Heydebreck ◽

W. Huber ◽

A. Poustka ◽

M. Vingron

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Expression Data ◽

Clear Separation ◽

New Class ◽

Class Discovery ◽

Discovery Method

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Identification of Ovarian Circular RNAs and Differential Expression Analysis between MeiShan and Large White Pigs

Animals ◽

10.3390/ani10071114 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1114

Author(s):

Guoming Liang ◽

Junyu Yan ◽

Jin Guo ◽

Zhonglin Tang

Keyword(s):

Gene Expression ◽

Differential Expression Analysis ◽

Enrichment Analysis ◽

Differentially Expressed ◽

Circular Rnas ◽

Reproductive Efficiency ◽

Gene Expression And Regulation ◽

Female Fecundity ◽

Large White ◽

Regulatory Functions

MeiShan and Large White pigs differ in their female fecundity. However, the mechanisms behind the gene expression and regulation that cause these differences remain unclear. In this study, we profiled circRNAs and identified 5,879 circRNAs from the ovaries of MeiShan and Large White pigs. Eighty-five circRNAs were differentially expressed between the two pig breeds. Of these, 37 were up-regulated and 48 were down-regulated in MeiShan pigs. Gene ontology enrichment analysis suggested that the differentially expressed circRNA were involved in the hormone-mediated signaling pathway. We verified that circSCIN and its parent gene, scinderin (SCIN), were differentially expressed by reverse transcription and quantitative PCR (RT-qPCR). Luciferase assays demonstrated that circSCIN can target and sponge miR-133 and miR-148a/b. The identification of differentially expressed circRNAs (DECs) and their regulatory functions increased our understanding of the differences in reproductive efficiency between MeiShan and Large White pigs.

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