Circular RNAs Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for CircRNA Clearance

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Feb 6

PMID 26848835

Citations 235

Authors

Erika Lasda

Roy Parker

Affiliations

Soon will be listed here.

Abstract

Backspliced circular RNAs (circRNAs) are prevalent in many eukaryotic systems and are spliced from thousands of different genes. Where examined, circRNAs are often highly stable and the mechanisms by which cells degrade and/or clear circRNAs from the cells are unknown. Here we investigated the possibility that cells can eliminate circRNAs into extracellular space, possibly within released vesicles such as exosomes and microvesicles. From three different cell lines and examining multiple circRNAs, we show that extracellular vesicle (EVs) preparations recovered from cell culture conditioned media contain established circRNAs. Moreover, these circRNAs are enriched over their linear counterparts within EV preparations when compared to the producing cells. This supports the idea that expulsion from cells into extracellular space, as by EVs release, can be a mechanism by which cells clear circRNAs. Moreover, since EVs can be taken up by other cells, excreted circRNAs could contribute to cell to cell communication.

Citing Articles

Circular RNAs in cancer.

Guo Y, Huang Q, Heng Y, Zhou Y, Chen H, Xu C MedComm (2020). 2025; 6(2):e70079.

PMID: 39901896 PMC: 11788016. DOI: 10.1002/mco2.70079.

A review of the roles of exosomes in salivary gland diseases with an emphasis on primary Sjögren's syndrome.

Cui X, Liu L, Duan C, Mao S, Wang G, Li H J Dent Sci. 2025; 20(1):1-14.

PMID: 39873057 PMC: 11762945. DOI: 10.1016/j.jds.2024.10.001.

Circular RNA Formation and Degradation Are Not Directed by Universal Pathways.

Srinivasan A, Mroczko-Mlotek E, Wojciechowska M Int J Mol Sci. 2025; 26(2).

PMID: 39859439 PMC: 11766002. DOI: 10.3390/ijms26020726.

Prognostic analysis of SYTL4 in acute myeloid leukemia.

Xie K, Wei J Transl Cancer Res. 2024; 13(11):5995-6003.

PMID: 39697748 PMC: 11651733. DOI: 10.21037/tcr-24-758.

Defining the landscape of circRNAs in non-small cell lung cancer and their potential as liquid biopsy biomarkers: a complete review including current methods.

Pedraz-Valdunciel C, Rosell R Extracell Vesicles Circ Nucl Acids. 2024; 2(2):179-201.

PMID: 39697533 PMC: 11648509. DOI: 10.20517/evcna.2020.07.

References

Jeppesen D, Hvam M, Primdahl-Bengtson B, Boysen A, Whitehead B, Dyrskjot L . Comparative analysis of discrete exosome fractions obtained by differential centrifugation. J Extracell Vesicles. 2014; 3:25011. PMC: 4224706. DOI: 10.3402/jev.v3.25011. View

Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J . Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015; 25(8):981-4. PMC: 4528056. DOI: 10.1038/cr.2015.82. View

Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S . Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Mol Cell. 2015; 58(5):870-85. DOI: 10.1016/j.molcel.2015.03.027. View

Raposo G, Stoorvogel W . Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013; 200(4):373-83. PMC: 3575529. DOI: 10.1083/jcb.201211138. View

Thery C, Amigorena S, Raposo G, Clayton A . Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2008; Chapter 3:Unit 3.22. DOI: 10.1002/0471143030.cb0322s30. View

Arroyo J, Chevillet J, Kroh E, Ruf I, Pritchard C, Gibson D . Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011; 108(12):5003-8. PMC: 3064324. DOI: 10.1073/pnas.1019055108. View

Dragovic R, Gardiner C, Brooks A, Tannetta D, Ferguson D, Hole P . Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis. Nanomedicine. 2011; 7(6):780-8. PMC: 3280380. DOI: 10.1016/j.nano.2011.04.003. View

Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A . Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013; 495(7441):333-8. DOI: 10.1038/nature11928. View

Guo J, Agarwal V, Guo H, Bartel D . Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014; 15(7):409. PMC: 4165365. DOI: 10.1186/s13059-014-0409-z. View

10.

Liang D, Wilusz J . Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 2014; 28(20):2233-47. PMC: 4201285. DOI: 10.1101/gad.251926.114. View

11.

Salzman J, Gawad C, Wang P, Lacayo N, Brown P . Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012; 7(2):e30733. PMC: 3270023. DOI: 10.1371/journal.pone.0030733. View

12.

Taylor D, Shah S . Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes. Methods. 2015; 87:3-10. DOI: 10.1016/j.ymeth.2015.02.019. View

13.

Salzman J, Chen R, Olsen M, Wang P, Brown P . Cell-type specific features of circular RNA expression. PLoS Genet. 2013; 9(9):e1003777. PMC: 3764148. DOI: 10.1371/journal.pgen.1003777. View

14.

Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K, Vandesompele J . The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J Extracell Vesicles. 2014; 3. PMC: 4169610. DOI: 10.3402/jev.v3.24858. View

15.

Jeck W, Sorrentino J, Wang K, Slevin M, Burd C, Liu J . Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2012; 19(2):141-57. PMC: 3543092. DOI: 10.1261/rna.035667.112. View

16.

Hansen T, Wiklund E, Bramsen J, Villadsen S, Statham A, Clark S . miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011; 30(21):4414-22. PMC: 3230379. DOI: 10.1038/emboj.2011.359. View

17.

Hansen T, Jensen T, Clausen B, Bramsen J, Finsen B, Damgaard C . Natural RNA circles function as efficient microRNA sponges. Nature. 2013; 495(7441):384-8. DOI: 10.1038/nature11993. View

18.

Ashwal-Fluss R, Meyer M, Pamudurti N, Ivanov A, Bartok O, Hanan M . circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014; 56(1):55-66. DOI: 10.1016/j.molcel.2014.08.019. View

19.

Kalra H, Simpson R, Ji H, Aikawa E, Altevogt P, Askenase P . Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012; 10(12):e1001450. PMC: 3525526. DOI: 10.1371/journal.pbio.1001450. View

20.

Cocquerelle C, Mascrez B, Hetuin D, Bailleul B . Mis-splicing yields circular RNA molecules. FASEB J. 1993; 7(1):155-60. DOI: 10.1096/fasebj.7.1.7678559. View