4.6 Review

The emerging roles of circRNAs in cancer and oncology

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Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma: a study of younger patients from the MCL2 and MCL3 clinical trials

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Summary: Circular RNAs (circRNAs) show promise as prognostic biomarkers in mantle cell lymphoma (MCL); the circSCORE signature improves the identification of high-risk disease in younger patients receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplant.

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Article Gastroenterology & Hepatology

A Circular RNA, Cholangiocarcinoma-Associated Circular RNA 1, Contributes to Cholangiocarcinoma Progression, Induces Angiogenesis, and Disrupts Vascular Endothelial Barriers

Yi Xu et al.

Summary: The study revealed that circ-CCAC1 is upregulated in cholangiocarcinoma (CCA) cells and extracellular vesicles (EVs), and plays a crucial role in promoting CCA tumorigenesis and metastasis through various mechanisms.

HEPATOLOGY (2021)

Article Biochemistry & Molecular Biology

CircRNA-vgll3 promotes osteogenic differentiation of adipose-derived mesenchymal stem cells via modulating miRNA-dependent integrin α5 expression

Dandan Zhang et al.

Summary: ADSCs' osteogenic differentiation is regulated by circRNA-vgll3, which promotes ADSC osteogenesis through the circRNA-vgll3/miR-326-5p/Integrin Alpha 5 pathway. The study demonstrates that circRNA-vgll3 can enhance new bone formation, making it a potential effective therapeutic target in bone regenerative medicine.

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Article Chemistry, Medicinal

Serum Extracellular Vesicle-Derived circHIPK3 and circSMARCA5 Are Two Novel Diagnostic Biomarkers for Glioblastoma Multiforme

Michele Stella et al.

Summary: The study suggests that sEV-derived circSMARCA5 and circHIPK3 are potential diagnostic biomarkers for GBM, especially when combined with preoperative NLR, PLR, and LMR to improve diagnostic accuracy.

PHARMACEUTICALS (2021)

Article Cell Biology

FUS-induced circular RNA ZNF609 promotes tumorigenesis and progression via sponging miR-142-3p in lung cancer

Shaoxia Liu et al.

Summary: The research revealed that circZNF609 functions as an oncogenic circRNA, promoting lung cancer cell proliferation and migration by sequestering miR-142-3p, through mechanisms involving FUS RNA-binding protein and G protein subunit beta 2.

JOURNAL OF CELLULAR PHYSIOLOGY (2021)

Article Cell Biology

CircZNF609 promotes cell proliferation, migration, invasion, and glycolysis in nasopharyngeal carcinoma through regulating HRAS via miR-338-3p

Zhonglu Liu et al.

Summary: The study revealed that high expression of circZNF609 in nasopharyngeal carcinoma is associated with poor prognosis. Knockdown of circZNF609 inhibited NPC progression by suppressing cell proliferation, migration, invasion, and glycolysis, and miR-338-3p, which is low in NPC, exhibited anti-tumor effects by targeting HRAS. Additionally, circZNF609 acted as a competing endogenous RNA of miR-338-3p to regulate HRAS in NPC, suggesting a novel therapeutic strategy.

MOLECULAR AND CELLULAR BIOCHEMISTRY (2021)

Article Oncology

CircRNA EPHB4 modulates stem properties and proliferation of gliomas via sponging miR-637 and up-regulating SOX10

Chen Jin et al.

Summary: The study revealed that circEPHB4 can impact the stemness, proliferation, and glycolysis of glioma cells through regulating the miR-637/SOX10/Nestin axis, and thus predicting the overall survival of glioma patients.

MOLECULAR ONCOLOGY (2021)

Letter Clinical Neurology

Distinct circular RNA expression profiles in pediatric ependymomas

Ulvi Ahmadov et al.

Summary: The study revealed a significant downregulation of circRNAs in pediatric ependymomas, with different circRNA expression patterns correlated to clinical outcomes and characteristics. These findings suggest that circRNAs could potentially serve as diagnostic and prognostic biomarkers in the future.

BRAIN PATHOLOGY (2021)

Article Dermatology

Characterization of circular RNA transcriptomes in psoriasis and atopic dermatitis reveals disease-specific expression profiles

Liviu I. Moldovan et al.

Summary: Atopic dermatitis and psoriasis are chronic inflammatory skin diseases associated with various comorbidities. circRNA expression landscapes in lesional skin of both diseases show a global downregulation compared to healthy skin, with specific circRNAs potentially serving as biomarkers for distinguishing between the two conditions. Psoriasis exhibits more pronounced dysregulation of circRNAs compared to atopic dermatitis.

EXPERIMENTAL DERMATOLOGY (2021)

Article Biochemical Research Methods

Screening for functional circular RNAs using the CRISPR-Cas13 system

Siqi Li et al.

Summary: The study demonstrates that CRISPR-RfxCas13d can effectively discriminate circRNAs from mRNAs and has identified important circRNAs involved in cell growth, such as the pro-proliferative circFAM120A and the regulatory circMan1a2 in mouse embryo preimplantation development.

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Article Oncology

Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells

Theresa Jakobsen et al.

Summary: Multiple myeloma (MM) is a common hematological malignancy with no cure currently available. Research has shown that circular RNA (circRNA) expression patterns are related to IMiD sensitivity, but certain circRNAs are not direct drivers of IMiD resistance.

CANCERS (2021)

Article Oncology

Gene Expression Signatures of a Preclinical Mouse Model during Colorectal Cancer Progression under Low-Dose Metronomic Chemotherapy

Hung Ho-Xuan et al.

Summary: Colorectal cancer is a common cancer type with a high mortality rate, and chemotherapy often leads to chemo-resistance and tumor relapse. Low dose metronomic (LDM) therapy is a novel chemotherapeutic approach that may offer new potential therapeutic targets.

CANCERS (2021)

Review Biochemistry & Molecular Biology

Best practices to ensure robust investigation of circular RNAs: pitfalls and tips

Samantha Dodbele et al.

Summary: Circular RNAs (circRNAs) are a class of RNA with covalently linked ends, with most mature circRNAs expressed at low levels, but some having known physiological functions and higher expression levels. Research on this type of RNA requires consideration of method limitations and potential risks, and practical advice for robust identification, validation, and functional characterization is provided.

EMBO REPORTS (2021)

Article Biochemical Research Methods

Profiling of circRNAs using an enzyme-free digital counting method

Lasse Sommer Kristensen

Summary: Circular RNAs (circRNAs) have attracted attention as potential biomarkers in various human diseases, particularly in cancer. However, their circular nature presents challenges for detection and quantification, making accurate quantification methods a high priority. The enzyme-free and digital quantification method, NanoString nCounter, shows promise for circRNA detection.

METHODS (2021)

Article Biochemical Research Methods

Signal and noise in circRNA translation

T. B. Hansen

Summary: In recent years, circular RNAs (circRNAs) have become a new and attractive field of research in RNA biology and disease, with numerous studies focusing on circRNA biogenesis and function. Originally described as a subclass of cytoplasmic non-coding RNA, recent observations suggest circRNAs may serve as templates for protein production, leading to ongoing debates and the importance of rigorous data analysis and experimental setups to resolve controversies. Traditional experiments for detecting circRNA translation are outlined, along with guidelines for distinguishing signal from inherent noise, with many of these guidelines applicable to other aspects of non-canonical translation as well.

METHODS (2021)

Article Biotechnology & Applied Microbiology

Comprehensive profiling of circular RNAs with nanopore sequencing and CIRI-long

Jinyang Zhang et al.

Summary: This study presents a method for enrichment and full-length sequencing of circRNA isoforms using nanopore technology, allowing high-throughput detection and reconstruction of circRNAs. The developed algorithm, CIRI-long, accurately reconstructs the sequence of circRNAs from long-read sequencing data. Analysis of adult mouse brain samples identified diverse circRNA types, including a novel intronic self-ligated circRNA with special splicing and expression patterns.

NATURE BIOTECHNOLOGY (2021)

Article Cell Biology

Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling

Xinya Gao et al.

Summary: The activation of EGFR signalling in GBM is driven by a newly discovered secretory E-cadherin protein variant called C-E-Cad encoded by circular RNA. This mechanism promotes tumorigenicity in glioma stem cells and provides a promising approach for treating EGFR-driven GBM by enhancing the efficacy of anti-EGFR strategies.

NATURE CELL BIOLOGY (2021)

Article Medicine, Research & Experimental

CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells

Xiaoxue Jiang et al.

Summary: CircMEG3 is downregulated in human liver cancer and inhibits the growth and differentiation of liver cancer stem cells through various mechanisms, providing potential therapeutic targets for liver cancer treatment.

MOLECULAR THERAPY-NUCLEIC ACIDS (2021)

Article Oncology

CircRNA ZNF609 Knockdown Represses the Development of Non-Small Cell Lung Cancer via miR-623/FOXM1 Axis

Fanghan Wang et al.

Summary: The study revealed the significant role of circZNF609 in the development of NSCLC, showing that its overexpression is associated with lower overall survival. circZNF609 regulates NSCLC development by targeting miR-623 and FOXM1, and suppresses NSCLC growth by inhibiting miR623 and FOXM1.

CANCER MANAGEMENT AND RESEARCH (2021)

Article Cell Biology

CDR1as regulated by hnRNPM maintains stemness of periodontal ligament stem cells via miR-7/KLF4

Xiuge Gu et al.

Summary: CDR1as plays a role in maintaining the stemness of PDLSCs by regulating the expression of stemness-related genes. It interacts with hnRNPM and inhibits miR-7-mediated suppression of KLF4 expression to promote the expression of stemness-related genes in PDLSCs.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

Review Biotechnology & Applied Microbiology

Antisense technology: an overview and prospectus

Stanley T. Crooke et al.

Summary: Antisense technology is delivering on its promise to treat diseases by targeting RNA, with nine single-stranded ASO drugs approved for commercial use. In addition to rare diseases, ASOs in development are intended to treat common diseases and show potential for increased potency and performance.

NATURE REVIEWS DRUG DISCOVERY (2021)

Article Chemistry, Multidisciplinary

HNRNPL Circularizes ARHGAP35 to Produce an Oncogenic Protein

Yan Li et al.

Summary: This study identified a novel oncogenic circRNA called circARHGAP35 originating from the tumor suppressor gene ARHGAP35, which has antithetical expression and functions with linear ARHGAP35. CircARHGAP35 encodes a truncated protein without the Rho GAP domain, promoting cancer cell progression by interacting with TFII-I protein in the nucleus. HNRNPL facilitates the formation of circARHGAP35, which is associated with poor survival in cancer patients.

ADVANCED SCIENCE (2021)

Article Oncology

circATP2B1 Promotes Aerobic Glycolysis in Gastric Cancer Cells Through Regulation of the miR-326 Gene Cluster

Xihe Zhao et al.

Summary: The study identified that circATP2B1 promoted aerobic glycolysis and proliferation of gastric cancer cells by capturing miR-326-3p/miR-330-5p and reducing their suppression of PKM2. This novel molecular pathway in gastric cancer may offer additional targets for reversing cancer metabolic reprogramming and provide a potential strategy for targeted therapy.

FRONTIERS IN ONCOLOGY (2021)

Article Biochemistry & Molecular Biology

Overexpression-based detection of translatable circular RNAs is vulnerable to coexistent linear RNA byproducts

Yanyi Jiang et al.

Summary: In the study, the protein-coding potential of 30 human circRNAs was investigated using a circRNA over-expression system, revealing heterogeneous translation outputs and potential false translation signals. It was also found that linear RNA byproducts could lead to pseudo rolling circle translation signals, and non-AUG start codons may be involved in the translation initiation of circRNAs.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2021)

Review Biochemical Research Methods

Circular RNAs as microRNA sponges: evidence and controversies

Morten T. Jarlstad Olesen et al.

Summary: Gene expression in eukaryotic cells is a complex process regulated at transcriptional and post-transcriptional levels. miRs and circRNAs play key roles at the post-transcriptional level, with circRNAs acting as sponges for miRs to increase the expression of corresponding target genes.

NON-CODING GENOME (2021)

Article Biotechnology & Applied Microbiology

The RNA Atlas expands the catalog of human non-coding RNAs

Lucia Lorenzi et al.

Summary: The study identified numerous novel non-coding RNAs from 300 human tissues and cell lines, expanding the existing catalog of ncRNAs. By analyzing pre-mRNA abundance estimates from total RNA sequencing, the research revealed several microRNAs and long non-coding RNAs with potential roles in regulating protein-coding genes and pathways.

NATURE BIOTECHNOLOGY (2021)

Article Multidisciplinary Sciences

Nanopore sequencing of brain-derived full-length circRNAs reveals circRNA-specific exon usage, intron retention and microexons

Karim Rahimi et al.

Summary: Circular RNAs, a class of covalently joined non-coding RNAs, play functional roles in cellular processes and exhibit overlap with exons in linear mRNAs. Long-read sequencing techniques have been used to characterize circRNAs, revealing a large number of splicing events and proposing altered exon usage as a resistance mechanism to nonsense-mediated decay. The development of targeted long-read sequencing methods offers a comprehensive approach to understanding the structure and function of circRNAs.

NATURE COMMUNICATIONS (2021)

Article Cell Biology

Mammalian circular RNAs result largely from splicing errors

Chuan Xu et al.

Summary: Most circRNAs are found to be deleterious products of splicing errors, with only a small number being functional candidates. The production of circRNAs varies among different species, and overall, circRNAs lack evolutionary conservation.

CELL REPORTS (2021)

Article Cell Biology

CircUBAP2 Promotes MMP9-Mediated Oncogenic Effect via Sponging miR-194-3p in Hepatocellular Carcinoma

Boqiang Liu et al.

Summary: This study identified a novel circRNA, circUBAP2, in hepatocellular carcinoma (HCC) through bioinformatics analysis. CircUBAP2 was significantly upregulated in HCC tissues and correlated with aggressive clinical characteristics and poor prognosis. Functionally, circUBAP2 promoted cell proliferation, colony formation, migration, and invasion in vitro, and enhanced tumor growth and pulmonary metastasis in vivo. Mechanistically, circUBAP2 acted as a competing endogenous RNA (ceRNA) for miR-194-3p, thereby regulating the expression of MMP9 and promoting HCC progression. CircUBAP2 could potentially serve as a prognostic biomarker and therapeutic target for HCC patients.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Circular RNA ZNF609 promotes the malignant progression of glioma by regulating miR-1224-3p/PLK1 signaling

Senjie Du et al.

Summary: This study demonstrated that circ-ZNF609 is significantly upregulated in glioma and promotes tumor growth and metastasis by enhancing PLK1 expression through competitively binding miR-1224-3p. Inhibition of circ-ZNF609 could suppress glioma cell proliferation, migration and invasion, suggesting circ-ZNF609 as a potential therapeutic target for glioma.

JOURNAL OF CANCER (2021)

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Targeting circular RNAs as a therapeutic approach: current strategies and challenges

Alina T. He et al.

Summary: Significant progress has been made in circular RNA (circRNA) research in recent years. CircRNAs are considered potential therapeutic targets and can be manipulated through various strategies for gain-of-function or loss-of-function. Although still in the early stages, the CRISPR/Cas13 system shows promise in efficiently knocking down circRNAs.

SIGNAL TRANSDUCTION AND TARGETED THERAPY (2021)

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Circular RNA ZNF609 functions as a competing endogenous RNA in regulating E2F transcription factor 6 through competitively binding to microRNA-197-3p to promote the progression of cervical cancer progression

Qiao Gu et al.

Summary: Circ-ZNF609, as an oncogene, promotes the progression of cervical cancer by modulating the miR-197-3p/E2F6 axis. This finding provides a unique insight into the molecular mechanisms of cervical cancer and suggests a potential therapeutic target.

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CircZNF609/miR-134-5p/BTG-2 axis regulates proliferation and migration of glioma cell

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circSamd4 represses myogenic transcriptional activity of PUR proteins

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Kunal Das Mahapatra et al.

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CircRNA ZNF609 Knockdown Suppresses Cell Growth via Modulating miR-I88/ELF2 Axis in Nasopharyngeal Carcinoma

Mingyan Li et al.

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Ling-Ling Chen

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CircZNF609 is involved in the pathogenesis of focal segmental glomerulosclerosis by sponging miR-615-5p

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Lasse S. Kristensen et al.

NATURE COMMUNICATIONS (2020)

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Janina Breuer et al.

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Widespread and Functional RNA Circularization in Localized Prostate Cancer

Sujun Chen et al.

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GENOME RESEARCH (2019)

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RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo

R. Alexander Wesselhoeft et al.

MOLECULAR CELL (2019)

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Autophagic cell death restricts chromosomal instability during replicative crisis

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Human Survival Motor Neuron genes generate a vast repertoire of circular RNAs

Eric W. Ottesen et al.

NUCLEIC ACIDS RESEARCH (2019)

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Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity

Chu-Xiao Liu et al.

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CELL RESEARCH (2019)

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MOLECULAR CELL (2019)

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Circ-ZNF609 regulates G1-S progression in rhabdomyosarcoma

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ONCOGENE (2019)

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GENOME MEDICINE (2019)

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LIFE SCIENCE ALLIANCE (2019)

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Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation

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RNA BIOLOGY (2018)

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A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy

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CIRCULATION RESEARCH (2018)

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Upregulation of circ-UBAP2 predicts poor prognosis and promotes triple-negative breast cancer progression through the miR-661/MTA1 pathway

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2018)

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CELL DEATH AND DIFFERENTIATION (2017)

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RNA BIOLOGY (2017)

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JOURNAL OF MOLECULAR MEDICINE-JMM (2017)

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MOLECULAR CELL (2017)

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MOLECULAR CELL (2017)

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MOLECULAR CELL (2017)

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2017)

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Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1

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RNA BIOLOGY (2017)

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FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons

Lorenzo Errichelli et al.

NATURE COMMUNICATIONS (2017)

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Yawei Li et al.

EMBO REPORTS (2017)

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CELL RESEARCH (2017)

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RNA BIOLOGY (2016)

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CELL STEM CELL (2016)

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CELL REPORTS (2016)

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The RNA Binding Protein Quaking Regulates Formation of circRNAs

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Exon Skipping Is Correlated with Exon Circularization

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JOURNAL OF MOLECULAR BIOLOGY (2015)

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CLINICAL CHEMISTRY (2015)

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Complementary Sequence-Mediated Exon Circularization

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Short intronic repeat sequences facilitate circular RNA production

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GENES & DEVELOPMENT (2014)

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circRNA Biogenesis Competes with Pre-mRNA Splicing

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MOLECULAR CELL (2014)

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MOLECULAR CELL (2013)

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Natural RNA circles function as efficient microRNA sponges

Thomas B. Hansen et al.

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PLoS Genetics (2013)

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Zhizhong Li et al.

DEVELOPMENTAL CELL (2012)

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MOLECULAR ENDOCRINOLOGY (2012)

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