Circular RNA expression is abundant and correlated to aggressiveness in early-stage bladder cancer

Okholm, Trine Line Hauge; Nielsen, Morten Muhlig; Hamilton, Mark; Christensen, Lise-Lotte; Vang, Søren; Hedegaard, Jakob; Hansen, Thomas B.; Kjems, Jørgen; Dyrskjøt, Lars; Pedersen, Jakob Skou

doi:10.1038/s41525-017-0038-z

Cited by 97 publications

(119 citation statements)

References 73 publications

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“…CircCDYL is clinically interesting, because it is deregulated in diseases (9,44,45) , correlated to clinical outcomes (45) , and highly expressed in patient plasma samples (44) and exosomes (9) , indicating potential as a non-invasive biomarker. Sun et al suggested that circCDYL overexpression inhibits MYC at the protein level, but found no effect on MYC mRNA levels (58) , contrasting our findings here.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we found that circCDYL is highly expressed in patients with non-muscle invasive bladder cancer (NMIBC) and correlates positively with good prognosis independently of the parent gene (45) . Based on our findings here, we hypothesized that circCDYL possess regulatory functions in bladder cancer (BC) by binding RBPs.…”

Section: Circcdyl Interacts With Rbps In Bladder Cancer and Abundancementioning

confidence: 96%

“…To understand the regulatory potential of circRNA-RBP interactions in more depth, we focused our attention on circCDYL's interaction with RBPs. CircCDYL is one of the highest expressed circRNAs across tissues in both humans and mice (43) and is deregulated in diseases, including cancer and myotonic dystrophy (9,44,45) . However, little is known about its regulatory functions and its potential to interact with RBPs remains unexplored.…”

Section: Functional Studies Of Circcdyl-rbp Interactions In Hepg2mentioning

confidence: 99%

“…Positions of Alu repeats were obtained from the UCSC Browser RepeatMasker track as described in a previous study (45) . Alu repeat positions were intersected with flanking regions of circRNAs and non-circularizing exons from above.…”

Section: Alu Repeats In Intronsmentioning

confidence: 99%

“…Table 9). To choose which BC cell lines to use in the experiments, we evaluated the expression of circCDYL using CIRI2 (34) in total RNA-Seq data from eleven BC cell lines (45,57) , and chose J82 and UMUC3 based on cell line stability and high circCDYL expression levels (Supp. Figure 6D).…”

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confidence: 99%

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Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

Okholm

Sathe

Park

et al. 2020

Preprint

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Circular 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.

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Section: Discussionmentioning

confidence: 99%

Section: Circcdyl Interacts With Rbps In Bladder Cancer and Abundancementioning

confidence: 96%

Section: Functional Studies Of Circcdyl-rbp Interactions In Hepg2mentioning

confidence: 99%

Section: Alu Repeats In Intronsmentioning

confidence: 99%

mentioning

confidence: 99%

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Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

Okholm

Sathe

Park

et al. 2020

Preprint

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CircRNAs in gastric cancer: current research and potential clinical implications

Gao

et al. 2021

FEBS Letters

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Gastric cancer (GC) has a dismal prognosis and is also one of the most commonly diagnosed malignancies worldwide. circRNAs are covalently closed circular RNA molecules without 5′‐cap and a 3′‐tail, currently listed among the broad noncoding RNA family. circRNAs participate in a variety of pathophysiological processes relevant to human diseases, especially malignancies, including GC. Compelling evidence has shown that circRNAs can function by sponging miRNAs, interacting with RNA binding proteins, and encoding proteins or peptides. Yet, our current understanding of these RNA circles remains very limited. Here, we overview the biogenesis, characteristics, functions, and degradation of circRNAs. Moreover, we give an account of the circRNAs that have been linked with GC, describing their functions and mechanisms of action in the context of GC. Next, we discuss the potential value of circRNAs as diagnostic or prognostic GC biomarkers and summarize future prospects, important questions, and challenges of circRNA‐based therapeutics.

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Circular RNAs in childhood‐related diseases and cancers: A review

Mao

Guo

et al. 2020

Cell Biochemistry & Function

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Research into the diagnosis, treatment and prevention of childhood‐related diseases is the key to reducing their morbidity and mortality. Circular RNAs (circRNAs) play critical roles, both in physiology and pathology, and there is ample evidence to show that they play varying roles in tissue development and gene regulation. Studies on circRNAs in different childhood‐related diseases have confirmed their great potential for disease prevention and treatment. These breakthroughs highlight the pathological role of circRNAs in cancers, as well as cardiovascular and hereditary childhood illnesses. In this review, we summarize the role of circRNAs in childhood‐related diseases and cancer, and provide an update of the possible diagnostic and therapeutic application of circRNAs.

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Circular RNA expression is abundant and correlated to aggressiveness in early-stage bladder cancer

Cited by 97 publications

References 73 publications

Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

CircRNAs in gastric cancer: current research and potential clinical implications

Circular RNAs in childhood‐related diseases and cancers: A review

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