Circular RNAs pp 119-130 | Cite as

Circular RNAs in Blood

  • Angela Vea
  • Vicenta Llorente-Cortes
  • David de Gonzalo-Calvo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1087)


Recent advances in RNA sequencing and bioinformatic analysis have allowed the development of a new research field: circular RNAs (circRNAs). These members of the non-coding transcriptome are generated by backsplicing, which results in a covalently closed, single-stranded RNA molecule. To date, thousands of circRNAs have been identified in different human cell types. CircRNAs are evolutionarily conserved, highly stable, cell-/developmental stage-specific and have longer half-lives compared with linear RNAs. Interestingly, different studies have demonstrated that circRNAs are abundantly expressed in the bloodstream. In this chapter, we review the current knowledge of circRNA biology in blood cells and the cell-free compartment, including extracellular vesicles. The potential clinical application of blood circRNAs in the biomarker and therapy fields is also discussed. Finally, perspectives for future studies are proposed.


Circular RNA Blood Serum Plasma Extracellular vesicles 



DdG-C was a recipient of Juan de la Cierva-Incorporación grants from the Ministerio de Economía y Competitividad (IJCI-2016-29393). CIBER Cardiovascular (CB16/11/00403 to DdG-C and VL-C) is a project of the Instituto de Salud Carlos III.

VLl-C and DdG-C are members of the CardiolincTM network.

Competing Financial Interests

The authors declare no competing financial interests.


  1. 1.
    Chen LL (2016) The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17(4):205–211CrossRefPubMedGoogle Scholar
  2. 2.
    Memczak S, Jens M, Elefsinioti A et al (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495(7441):333–338CrossRefPubMedGoogle Scholar
  3. 3.
    Conn SJ, Pillman KA, Toubia J et al (2015) The RNA binding protein quaking regulates formation of circRNAs. Cell 160(6):1125–1134CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang XO, Wang HB, Zhang Y et al (2014) Complementary sequence-mediated exon circularization. Cell 159(1):134–147CrossRefPubMedGoogle Scholar
  5. 5.
    Khan MA, Reckman YJ, Aufiero S et al (2016) RBM20 regulates circular RNA production from the Titin gene. Circ Res 119(9):996–1003Google Scholar
  6. 6.
    Salzman J, Chen RE, Olsen MN et al (2013) Cell-type specific features of circular RNA expression. PLoS Genet 9(9):e1003777CrossRefPubMedGoogle Scholar
  7. 7.
    Jeck WR, Sorrentino JA, Wang K et al (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19(2):141–157CrossRefPubMedGoogle Scholar
  8. 8.
    Bonizzato A, Gaffo E, Te Kronnie G et al (2016) CircRNAs in hematopoiesis and hematological malignancies. Blood Cancer J 6(10):e483CrossRefPubMedGoogle Scholar
  9. 9.
    Tuck AC, Tollervey D (2011) RNA in pieces. Trends Genet 27(10):422–432CrossRefGoogle Scholar
  10. 10.
    Sanger HL, Klotz G, Riesner D et al (1976) Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A 73(11):3852–3856CrossRefPubMedGoogle Scholar
  11. 11.
    Cocquerelle C, Mascrez B, Hetuin D et al (1993) Mis-splicing yields circular RNA molecules. FASEB J 7(1):155–160CrossRefPubMedGoogle Scholar
  12. 12.
    Kos A, Dijkema R, Arnberg AC et al (1986) The hepatitis delta (delta) virus possesses a circular RNA. Nature 323(6088):558–560CrossRefPubMedGoogle Scholar
  13. 13.
    Salzman J, Gawad C, Wang PL et al (2012) Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 7(2):e30733CrossRefPubMedGoogle Scholar
  14. 14.
    Li Z, Huang C, Bao C et al (2015) Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22(3):256–264CrossRefGoogle Scholar
  15. 15.
    Rybak-Wolf A, Stottmeister C, Glazar P et al (2015) Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 58(5):870–885CrossRefGoogle Scholar
  16. 16.
    Cao S, Wei D, Li X et al (2017) Novel circular RNA expression profiles reflect progression of patients with hypopharyngeal squamous cell carcinoma. Oncotarget 8(28):45367–45379CrossRefPubMedGoogle Scholar
  17. 17.
    Xu T, Wu J, Han P et al (2017) Circular RNA expression profiles and features in human tissues: a study using RNA-seq data. BMC Genomics 18(Suppl 6):680CrossRefPubMedGoogle Scholar
  18. 18.
    Hansen TB, Jensen TI, Clausen BH et al (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388CrossRefPubMedGoogle Scholar
  19. 19.
    Pan RY, Liu P, Zhou HT et al (2017) Circular RNAs promote TRPM3 expression by inhibiting hsa-miR-130a-3p in coronary artery disease patients. Oncotarget 8(36):60280–60290CrossRefPubMedGoogle Scholar
  20. 20.
    Wang K, Sun Y, Tao W et al (2017) Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. Cancer Lett 394:1–12CrossRefPubMedGoogle Scholar
  21. 21.
    Conn VM, Hugouvieux V, Nayak A et al (2017) A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat Plants 3:17053CrossRefGoogle Scholar
  22. 22.
    Du WW, Yang W, Liu E et al (2016) Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res 44(6):2846–2858CrossRefPubMedGoogle Scholar
  23. 23.
    Yang Y, Fan X, Mao M et al (2017) Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res 27(5):626–641CrossRefPubMedGoogle Scholar
  24. 24.
    Devaux Y, Creemers EE, Boon RA et al (2017) Circular RNAs in heart failure. Eur J Heart Fail 19(6):701–709CrossRefPubMedGoogle Scholar
  25. 25.
    Xu Z, Yan Y, Zeng S et al (2018) Circular RNAs: clinical relevance in cancer. Oncotarget 9(1):1444–1460Google Scholar
  26. 26.
    Memczak S, Papavasileiou P, Peters O et al (2015) Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS One 10(10):e0141214CrossRefPubMedGoogle Scholar
  27. 27.
    Salgado-Somoza A, Zhang L, Vausort M et al (2017) The circular RNA MICRA for risk stratification after myocardial infarction. Int J Cardiol Heart Vasc 17:33–36PubMedCentralPubMedGoogle Scholar
  28. 28.
    Teng L, Chen Y, Chen H et al (2017) Circular RNA hsa_circ_0021001 in peripheral blood: a potential novel biomarker in the screening of intracranial aneurysm. Oncotarget 8(63):107125–107133CrossRefPubMedGoogle Scholar
  29. 29.
    Vausort M, Salgado-Somoza A, Zhang L et al (2016) Myocardial infarction-associated circular RNA predicting left ventricular dysfunction. J Am Coll Cardiol 68(11):1247–1248CrossRefGoogle Scholar
  30. 30.
    Zhao Z, Li X, Gao C et al (2017) Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Sci Rep 7:39918CrossRefPubMedGoogle Scholar
  31. 31.
    Zhao Z, Li X, Jian D et al (2017) Hsa_circ_0054633 in peripheral blood can be used as a diagnostic biomarker of pre-diabetes and type 2 diabetes mellitus. Acta Diabetol 54(3):237–245CrossRefPubMedGoogle Scholar
  32. 32.
    Broadbent KM, Park D, Wolf AR et al (2011) A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs. Genome Biol 12(6):R56CrossRefPubMedGoogle Scholar
  33. 33.
    Alhasan AA, Izuogu OG, Al-Balool HH et al (2016) Circular RNA enrichment in platelets is a signature of transcriptome degradation. Blood 127(9):e1–e11CrossRefPubMedGoogle Scholar
  34. 34.
    Maass PG, Glazar P, Memczak S et al (2017) A map of human circular RNAs in clinically relevant tissues. J Mol Med (Berl) 95(11):1179–1189CrossRefGoogle Scholar
  35. 35.
    Sunderland N, Skroblin P, Barwari T et al (2017) MicroRNA biomarkers and platelet reactivity: the clot thickens. Circ Res 120(2):418–435CrossRefPubMedGoogle Scholar
  36. 36.
    Preusser C, Hung LH, Schneider T et al (2018) Selective release of circRNAs in platelet-derived extracellular vesicles. J Extracell Vesicles 7(1):1424473CrossRefPubMedGoogle Scholar
  37. 37.
    Ouyang Q, Wu J, Jiang Z et al (2017) Microarray expression profile of circular RNAs in peripheral blood mononuclear cells from rheumatoid arthritis patients. Cell Physiol Biochem 42(2):651–659CrossRefGoogle Scholar
  38. 38.
    Zhang Y, Zhang Y, Li X et al (2017) Microarray analysis of circular RNA expression patterns in polarized macrophages. Int J Mol Med 39(2):373–379CrossRefPubMedGoogle Scholar
  39. 39.
    Ng WL, Marinov GK, Liau ES et al (2016) Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway. RNA Biol 13(9):861–871CrossRefPubMedGoogle Scholar
  40. 40.
    Wang YH, Yu XH, Luo SS et al (2015) Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing. Immun Ageing 12:17CrossRefPubMedGoogle Scholar
  41. 41.
    Koh W, Pan W, Gawad C et al (2014) Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proc Natl Acad Sci U S A 111(20):7361–7366CrossRefPubMedGoogle Scholar
  42. 42.
    Li S, Teng S, Xu J et al (2018) Microarray is an efficient tool for circRNA profiling. Brief Bioinform.
  43. 43.
    Li Y, Zheng Q, Bao C et al (2015) Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 25(8):981–984CrossRefPubMedGoogle Scholar
  44. 44.
    Li P, Chen S, Chen H et al (2015) Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta 444:132–136CrossRefPubMedGoogle Scholar
  45. 45.
    Li T, Shao Y, Fu L et al (2018) Plasma circular RNA profiling of patients with gastric cancer and their droplet digital RT-PCR detection. J Mol Med (Berl) 96(1):85–96CrossRefGoogle Scholar
  46. 46.
    Bazan HA, Hatfield SA, Brug A et al (2017) Carotid plaque rupture is accompanied by an increase in the ratio of serum circR-284 to miR-221 levels. Circ Cardiovasc Genet 10(4):e001720CrossRefPubMedGoogle Scholar
  47. 47.
    Chen S, Li T, Zhao Q et al (2017) Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer. Clin Chim Acta 466:167–171CrossRefPubMedGoogle Scholar
  48. 48.
    Huang M, He YR, Liang LC et al (2017) Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer. World J Gastroenterol 23(34):6330–6338CrossRefPubMedGoogle Scholar
  49. 49.
    Ji W, Qiu C, Wang M et al (2018) Hsa_circ_0001649: a circular RNA and potential novel biomarker for colorectal cancer. Biochem Biophys Res Commun 497(1):122–126CrossRefGoogle Scholar
  50. 50.
    Li WH, Song YC, Zhang H et al (2017) Decreased expression of Hsa_circ_00001649 in gastric cancer and its clinical significance. Dis Markers 2017:4587698PubMedCentralPubMedGoogle Scholar
  51. 51.
    Lu R, Shao Y, Ye G et al (2017) Low expression of hsa_circ_0006633 in human gastric cancer and its clinical significances. Tumour Biol 39(6):1010428317704175CrossRefGoogle Scholar
  52. 52.
    Sun H, Tang W, Rong D et al (2018) Hsa_circ_0000520, a potential new circular RNA biomarker, is involved in gastric carcinoma. Cancer Biomark 21(2):299–306CrossRefPubMedGoogle Scholar
  53. 53.
    Yin WB, Yan MG, Fang X et al (2017) Circulating circular RNA hsa_circ_0001785 acts as a diagnostic biomarker for breast cancer detection. Clin Chim Acta S0009–8981(17):30407–30402Google Scholar
  54. 54.
    Zhang SJ, Chen X, Li CP et al (2017) Identification and characterization of circular RNAs as a new class of putative biomarkers in diabetes retinopathy. Invest Ophthalmol Vis Sci 58(14):6500–6509CrossRefPubMedGoogle Scholar
  55. 55.
    Zhao Q, Chen S, Li T et al (2018) Clinical values of circular RNA 0000181 in the screening of gastric cancer. J Clin Lab Anal 32(4): e22333CrossRefGoogle Scholar
  56. 56.
    Zheng J, Li Z, Wang T et al (2017) Microarray expression profile of circular RNAs in plasma from primary biliary cholangitis patients. Cell Physiol Biochem 44(4):1271–1281CrossRefGoogle Scholar
  57. 57.
    Zhang J, Xu Y, Xu S et al (2018) Plasma circular RNAs, Hsa_circRNA_025016, predict postoperative atrial fibrillation after isolated off-pump coronary artery bypass grafting. J Am Heart Assoc 7:e006642PubMedCentralPubMedGoogle Scholar
  58. 58.
    de Gonzalo-Calvo D, Cenarro A, Garlaschelli K et al (2017) Translating the microRNA signature of microvesicles derived from human coronary artery smooth muscle cells in patients with familial hypercholesterolemia and coronary artery disease. J Mol Cell Cardiol 106:55–67CrossRefGoogle Scholar
  59. 59.
    Hergenreider E, Heydt S, Treguer K et al (2012) Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14(3):249–256CrossRefGoogle Scholar
  60. 60.
    Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F et al (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980CrossRefPubMedGoogle Scholar
  61. 61.
    Lasda E, Parker R (2016) Circular RNAs co-precipitate with extracellular vesicles: a possible mechanism for circRNA clearance. PLoS One 11(2):e0148407CrossRefPubMedGoogle Scholar
  62. 62.
    Dou Y, Cha DJ, Franklin JL et al (2016) Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes. Sci Rep 6:37982CrossRefPubMedGoogle Scholar
  63. 63.
    de Gonzalo-Calvo D, Quezada M, Campuzano O et al (2017) Familial dilated cardiomyopathy: a multidisciplinary entity, from basic screening to novel circulating biomarkers. Int J Cardiol 228:870–880CrossRefGoogle Scholar
  64. 64.
    de Gonzalo-Calvo D, Iglesias-Gutierrez E, Llorente-Cortes V (2017) Epigenetic biomarkers and cardiovascular disease: circulating MicroRNAs. Rev Esp Cardiol (Engl Ed) 70(9):763–769CrossRefGoogle Scholar
  65. 65.
    Umu SU, Langseth H, Bucher-Johannessen C et al (2018) A comprehensive profile of circulating RNAs in human serum. RNA Biol 15(2):242–250CrossRefPubMedGoogle Scholar
  66. 66.
    Li W, Zhong C, Jiao J et al (2017) Characterization of hsa_circ_0004277 as a new biomarker for acute myeloid leukemia via circular RNA profile and bioinformatics analysis. Int J Mol Sci 18(3):597CrossRefGoogle Scholar
  67. 67.
    Li H, Li K, Lai W et al (2018) Comprehensive circular RNA profiles in plasma reveals that circular RNAs can be used as novel biomarkers for systemic lupus erythematosus. Clin Chim Acta 480:17–25CrossRefPubMedGoogle Scholar
  68. 68.
    Zhuang ZG, Zhang JA, Luo HL et al (2017) The circular RNA of peripheral blood mononuclear cells: Hsa_circ_0005836 as a new diagnostic biomarker and therapeutic target of active pulmonary tuberculosis. Mol Immunol 90:264–272CrossRefGoogle Scholar
  69. 69.
    Guarnerio J, Bezzi M, Jeong JC et al (2016) Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 165(2):289–302CrossRefPubMedGoogle Scholar
  70. 70.
    Gupta SK, Garg A, Bar C et al (2018) Quaking inhibits doxorubicin-mediated cardiotoxicity through regulation of cardiac circular RNA expression. Circ Res 122(2):246–254CrossRefGoogle Scholar
  71. 71.
    Bang C, Batkai S, Dangwal S et al (2014) Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 124(5):2136–2146CrossRefPubMedGoogle Scholar
  72. 72.
    Schneider T, Hung LH, Schreiner S et al (2016) CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs. Sci Rep 6:31313CrossRefPubMedGoogle Scholar
  73. 73.
    Arroyo JD, Chevillet JR, Kroh EM et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108(12):5003–5008CrossRefPubMedGoogle Scholar
  74. 74.
    Vickers KC, Palmisano BT, Shoucri BM et al (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13(4):423–433CrossRefPubMedGoogle Scholar
  75. 75.
    Jeck WR, Sharpless NE (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32(5):453–461CrossRefPubMedGoogle Scholar
  76. 76.
    Devaux Y (2017) Transcriptome of blood cells as a reservoir of cardiovascular biomarkers. Biochim Biophys Acta 1864(1):209–216CrossRefGoogle Scholar
  77. 77.
    Szabo L, Salzman J (2016) Detecting circular RNAs: bioinformatic and experimental challenges. Nat Rev Genet 17(11):679–692CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Angela Vea
    • 1
  • Vicenta Llorente-Cortes
    • 1
    • 2
    • 3
  • David de Gonzalo-Calvo
    • 1
    • 2
    • 3
  1. 1.Biomedical Research Institute Sant Pau (IIB Sant Pau)BarcelonaSpain
  2. 2.Institute of Biomedical Research of Barcelona (IIBB) – Spanish National Research Council (CSIC)BarcelonaSpain
  3. 3.CIBERCVInstitute of Health Carlos IIIMadridSpain

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