The potential of using blood circular RNA as liquid biopsy biomarker for human diseases

Abstract

Circular RNA (circRNA) is a novel class of singlestranded RNAs with a closed loop structure. The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing. Their expression is dynamically regulated and shows spatiotemporal patterns among cell types, tissues and developmental stages. CircRNAs have important biological functions in many physiological processes, and their aberrant expression is implicated in many human diseases. Due to their high stability, circRNAs are becoming promising biomarkers in many human diseases, such as cardiovascular diseases, autoimmune diseases and human cancers. In this review, we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases. We highlight their abundant expression, essential biological functions and significant correlations to human diseases in various components of peripheral blood, including whole blood, blood cells and extracellular vesicles. In addition, we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis.

Keywords

peripheral blood circular RNA / liquid psy / human diseases / translational biomarkers

References

[1] Abdelmohsen K, Panda AC, Munk R, Grammatikakis I, Dudekula DB, De S, Kim J, Noh J, Kim K, Martindale JL (2017) Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol 14:361–369

[2] Agirre X, Meydan C, Jiang Y, Garate L, Doane AS, Li Z, Verma A, Paiva B, Martín-Subero JI, Elemento O (2019) Long noncoding RNAs discriminate the stages and gene regulatory states of human humoral immune response. Nat Commun 10:821

[3] Ahadi S, Zhou W, Rose S, Sailani RM, Contrepois K, Avina M, Ashland M, Brunet A, Snyder M (2020) Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat Med 26:83–90

[4] Aktaş T, Ilık İ, Maticzka D, Bhardwaj V, Rodrigues C, Mittler G, Manke T, Backofen R, Akhtar A (2017) DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature 544:115–119

[5] Alhasan AA, Izuogu OG, Al-Balool HH, Steyn JS, Evans A, Colzani M, Ghevaert C, Mountford JC, Marenah L, Elliott DJ (2016) Circular RNA enrichment in platelets is a signature of transcriptome degradation. Blood 127:e1–e11

[6] Anderson ST, Kaforou M, Brent AJ, Wright VJ, Banwell CM, Chagaluka G, Crampin AC, Dockrell HM, French N, Hamilton MS (2014) Diagnosis of childhood tuberculosis and host RNA expression in Africa. N Engl J Med 370:1712–1723

[7] Anfossi S, Babayan A, Pantel K, Calin GA (2018) Clinical utility of circulating non-coding RNAs—an update. Nat Rev Clin Oncol 15:541–563

[8] Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA 108:5003–5008

[9] Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, Evantal N, Memczak S, Rajewsky N, Kadener S (2014) CircRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56:55–66

[10] Aufiero S, Reckman YJ, Pinto YM, Creemers EE (2019) Circular RNAs open a new chapter in cardiovascular biology. Nat Rev Cardiol 16:503–514

[11] Awan FM, Yang BB, Naz A, Hanif A, Ikram A, Obaid A, Malik A, Janjua HA, Ali A, Sharif S (2020) The emerging role and significance of circular RNAs in viral infections and antiviral immune responses: possible implication as theranostic agents. RNA Biol. https://doi.org/10.1080/15476286.2020.1790198

[12] Bahn JH, Zhang Q, Li F, Chan TM, Lin X, Kim Y, Wong DTW, Xiao X (2014) The landscape of microRNA, piwi-interacting RNA, and circular RNA in human saliva. Clin Chem 61:221–230

[13] Bao X, He X, Zheng S, Sun J, Luo Y, Tan R, Zhao J, Zhong F, Zhang L (2019) Up-regulation of circular RNA hsa_circ_0037909 promotes essential hypertension. J Clin Lab Anal 33:e22853

[14] Bao X, Zheng S, Mao S, Gu T, Liu S, Sun J, Zhang L (2018) A potential risk factor of essential hypertension in case–control study: circular RNA hsa_circ_0037911. Biochem Biophys Res Commun 498:789–794

[15] Barrett SP, Wang PL, Salzman J (2015) Circular RNA biogenesis can proceed through an exon-containing lariat precursor. eLife 4: e07540

[16] Beltrán-García J, Osca-Verdegal R, Nacher-Sendra E, Pallardó FV, García-Giménez JL (2020) Circular RNAs in sepsis: biogenesis, function, and clinical significance. Cells 9:1544

[17] Best MG, Vancura A, Wurdinger T (2017) Platelet RNA as a circulating biomarker trove for cancer diagnostics. J Thromb Haemost 15:1295–1306

[18] Best MG, Wesseling P, Wurdinger T (2018) Tumor-educated platelets as a noninvasive biomarker source for cancer detection and progression monitoring. Cancer Res 78:3407–3412

[19] Blauwkamp TA, Thair S, Rosen MJ, Blair L, Lindner MS, Vilfan ID, Kawli T, Christians FC, Venkatasubrahmanyam S, Wall GD (2019) Analytical and clinical validation of a microbial cell-free DNA sequencing test for infectious disease. Nat Microbiol 4:663–674

[20] Bloom CI, Graham CM, Berry MP, Rozakeas F, Redford PS, Wang Y, Xu Z, Wilkinson KA, Wilkinson RJ, Kendrick Y (2013) Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers. PLoS ONE 8:e70630

[21] Bloom RD, Bromberg JS, Poggio ED, Bunnapradist S, Langone AJ, Sood P, Matas AJ, Mehta S, Mannon RB, Sharfuddin A (2017) Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol 28:2221–2232

[22] Bullinger L, Döhner K, Bair E, Fröhling S, Schlenk RF, Tibshirani R, Döhner H, Pollack JR (2004) Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:1605–1616

[23] Burnham P, Dadhania D, Heyang M, Chen F, Westblade LF, Suthanthiran M, Lee J, Vlaminck I (2018) Urinary cell-free DNA is a versatile analyte for monitoring infections of the urinary tract. Nat Commun 9:2412

[24] Byron SA, Keuren-Jensen KR, Engelthaler DM, Carpten JD, Craig DW (2016) Translating RNA sequencing into clinical diagnostics: opportunities and challenges. Nat Rev Genet 17:257–271

[25] Cadena C, Hur S (2017) Antiviral immunity and circular RNA: no end in sight. Mol Cell 67:163–164

[26] Cai Z, Fan Y, Zhang Z, Lu C, Zhu Z, Jiang T, Shan T, Peng Y (2020) VirusCircBase: a database of virus circular RNAs. Brief Bioin form. https://doi.org/10.1093/bib/bbaa052

[27] Cescon DW, Bratman SV, Chan SM, Siu LL (2020) Circulating tumor DNA and liquid biopsy in oncology. Nat Cancer 1:276–290

[28] Chaussabel D (2015) Assessment of immune status using blood transcriptomics and potential implications for global health. Semin Immunol 27:58–66

[29] Chaussabel D, Baldwin N (2014) Democratizing systems immunology with modular transcriptional repertoire analyses. Nat Rev Immunol 14:271–280

[30] Chen A, Zhong L, Ju K, Lu T, Lv J, Cao H (2020) Plasmatic circRNA predicting the occurrence of human glioblastoma. Cancer Manag Res 12:2917–2923

[31] Chen GY, Chen R, Ahmad S, Verma R, Kasturi S, Amaya L, Broughton JP, Kim J, Cadena C, Pulendran B (2019) N₆-methyladenosine modification controls circular RNA immunity. Mol Cell 76:96–109.e109

[32] Chen GY, Kim MV, Chen X, Batista PJ, Aoyama S, Wilusz JE, Iwasaki A, Chang HY (2017) Sensing self and foreign circular RNAs by intron identity. Mol Cell 67:228–238

[33] Chen GY, Satpathy AT, Chang HY (2017) Gene regulation in the immune system by long noncoding RNAs. Nat Immunol 18:962–972

[34] Chen J, Zang Z, Braun U, Schwarz K, Harneit A, Kremer T, Ma R, Schweiger J, Moessnang C, Geiger L (2020) Association of a reproducible epigenetic risk profile for schizophrenia with brain methylation and function. JAMA Psychiatry 77(6):628–636

[35] Chen L-L (2016) The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17:205–211

[36] Chen L-L (2020) The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol 21:1–16

[37] Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam H, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE (2012) Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 148:1293–1307

[38] Chen R, Xia L, Tu K, Duan M, Kukurba K, Li-Pook-Than J, Xie D, Snyder M (2018) Longitudinal personal DNA methylome dynamics in a human with a chronic condition. Nat Med 24:1930–1939

[39] Chen S, Huang V, Xu X, Livingstone J, Soares F, Jeon J, Zeng Y, Hua J, Petricca J, Guo H (2019) Widespread and functional RNA circularization in localized prostate cancer. Cell 176:831843.e822

[40] Chen S, Li T, Zhao Q, Xiao B, Guo J (2017) Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer. Clin Chim Acta 466:167–171

[41] Chen W, Quan Y, Fan S, Wang H, Liang J, Huang L, Chen L, Liu Q, He P, Ye Y (2020) Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression. Cancer Lett 475:119–128

[42] Chen X, Chen RX, Wei WS, Li YH, Feng ZH, Tan L, Chen JW, Yuan GJ, Chen SL, Guo SJ (2018) PRMT5 circular RNA promotes metastasis of urothelial carcinoma of the bladder through sponging miR-30c to induce epithelial–mesenchymal transition. Clin Cancer Res 24:6319–6330

[43] Chen X, Yang T, Wang W, Xi W, Zhang T, Li Q, Yang A, Wang T (2019) Circular RNAs in immune responses and immune diseases. Theranostics 9:588–607

[44] Chen Y, Li C, Tan C, Liu X (2016) Circular RNAs: a new frontier in the study of human diseases. J Med Genet 53:359–365

[45] Chen Y-J, Chen C-Y, Mai T-L, Chuang C-F, Chen Y-C, Gupta SK, Yen L, Wang Y-D, Chuang T-J (2020) Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA–microRNA–mRNA regulatory axes in autism. Genome Res 30:375–391

[46] Chi BJ, Zhao DM, Liu L, Yin XZ, Wang FF, Bi S, Gui SL, Zhou SB, Qin WB, Wu DM (2019) Downregulation of hsa_circ_0000285 serves as a prognostic biomarker for bladder cancer and is involved in cisplatin resistance. Neoplasma 66:197–202

[47] Ciarloni L, Ehrensberger S, Imaizumi N, Monnier-Benoit S, Nichita C, Myung S-J, Kim J, Song S, Kim T, van der Weg B (2016) Development and clinical validation of a blood test based on 29-gene expression for early detection of colorectal cancer. Clin Cancer Res 22:4604–4611

[48] Ciarloni, L., Hosseinian, S., Monnier-Benoit, S., Imaizumi, N., Dorta, G., Ruegg, C., and Group, O.b.o.t (2015) Discovery of a 29-gene panel in peripheral blood mononuclear cells for the detection of colorectal cancer and adenomas using high throughput real-time PCR. PLoS ONE 10:e0123904

[49] Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ (2015) The RNA binding protein quaking regulates formation of circRNAs. Cell 160:1125–1134

[50] Correia CN, Nalpas NC, McLoughlin KE, Browne JA, Gordon SV, MacHugh DE, Shaughnessy RG (2017) Circulating microRNAs as potential biomarkers of infectious disease. Front Immunol 8:118

[51] Crutchfield CA, Thomas SN, Sokoll LJ, Chan DW (2016) Advances in mass spectrometry-based clinical biomarker discovery. Clin Proteomics 13:1

[52] Cui C, Yang J, Li X, Liu D, Fu L, Wang X (2020) Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance. Mol Cancer 19:58

[53] de Fraipont F, Gazzeri S, Cho WC, Eymin B (2019) Circular RNAs and RNA splice variants as biomarkers for prognosis and therapeutic response in the liquid biopsies of lung cancer patients. Front Genet 10:390

[54] Ding C, Yi X, Wu X, Bu X, Wang D, Wu Z, Zhang G, Gu J, Kang D (2020) Exosome-mediated transfer of circRNA CircNFIX enhances temozolomide resistance in glioma. Cancer Lett 479:1–12

[55] Dolinar A, Koritnik B, Glavac D, Ravnik-Glavac M (2019) Circular RNAs as potential blood biomarkers in amyotrophic lateral sclerosis. Mol Neurobiol 56:8052–8062

[56] Du WW, Fang L, Yang W, Wu N, Awan FM, Yang Z, Yang BB (2016) Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ 24:357–370

[57] Du WW, Yang W, Chen Y, Wu Z-K, Foster FS, Yang Z, Li X, Yang BB (2017) Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. Eur Heart J 38:1402–1412

[58] Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB (2016) Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res 44:2846–2858

[59] Dube U, Del-Aguila JL, Li Z, Budde JP, Jiang S, Hsu S, Ibanez L, Fernandez M, Farias F, Norton J (2019) An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Nat Neurosci 22:1–10

[60] Dvinge H, Ries RE, Ilagan JO, Stirewalt DL, Meshinchi S, Bradley RK (2014) Sample processing obscures cancer-specific alterations in leukemic transcriptomes. Proc Natl Acad Sci USA 111:16802–16807

[61] Enuka Y, Lauriola M, Feldman ME, Sas-Chen A, Ulitsky I, Yarden Y (2015) Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res 44:1370–1383

[62] Errichelli L, Modigliani S, Laneve P, Colantoni A, Legnini I, Capauto D, Rosa A, Santis R, Scarfò R, Peruzzi G (2017) FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons. Nat Commun 8:14741

[63] Esmail H, Cobelens F, Goletti D (2020) Transcriptional biomarkers for predicting development of tuberculosis: progress and clinical considerations. Eur Respir J 55:1901957

[64] Fan L, Cao Q, Liu J, Zhang J, Li B (2019) Circular RNA profiling and its potential for esophageal squamous cell cancer diagnosis and prognosis. Mol Cancer 18:16

[65] Fang Y, Wang X, Li W, Han J, Jin J, Su F, Zhang J, Huang W, Xiao F, Pan Q (2018) Screening of circular RNAs and validation of circANKRD36 associated with inflammation in patients with type 2 diabetes mellitus. Int J Mol Med 42:1865–1874

[66] Fehlmann T, Kahraman M, Ludwig N, Backes C, Galata V, Keller V, Geffers L, Mercaldo N, Hornung D, Weis T (2020) Evaluating the use of circulating microRNA profiles for lung cancer detection in symptomatic patients. JAMA Oncol 6(5):714–723

[67] Fei T, Chen Y, Xiao T, Li W, Cato L, Zhang P, Cotter MB, Bowden M, Lis RT, Zhao SG (2017) Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proc Natl Acad Sci USA 114:E5207–E5215

[68] Fischer JW, Busa VF, Shao Y, Leung AKL (2020) Structure-mediated RNA decay by UPF1 and G3BP1. Mol Cell 78:70–84.e76

[69] Fritz JV, Heintz-Buschart A, Ghosal A, Wampach L, Etheridge A, Galas D, Wilmes P (2016) Sources and functions of extracellular small RNAs in human circulation. Annu Rev Nutr 36:301–336

[70] Fu Y, Wang J, Qiao J, Yi Z (2019) Signature of circular RNAs in peripheral blood mononuclear cells from patients with active tuberculosis. J Cell Mol Med 23:1917–1925

[71] Gaffo E, Boldrin E, Molin A, Bresolin S, Bonizzato A, Trentin L, Frasson C, Debatin K-M, Meyer LH, te Kronnie (2019) Circular RNA differential expression in blood cell populations and exploration of circRNA deregulation in pediatric acute lymphoblastic leukemia. Sci Rep 9:14670

[72] Gao Y, Zhao F (2018) Computational strategies for exploring circular RNAs. Trends Genet. https://doi.org/10.1016/j.tig.2017.12.016

[73] Geng H-H, Li R, Su Y-M, Xiao J, Pan M, Cai X-X, Ji X-P (2016) The circular RNA Cdr1as promotes myocardial infarction by mediating the regulation of miR-7a on its target genes expression. PLoS ONE 11:e0151753

[74] Ghods F (2018) Circular RNA in saliva. Adv Exp Med Biol 1087:131–139

[75] Giraldo NA, Becht E, Vano Y, Petitprez F, Lacroix L, Validire P, Sanchez-Salas R, Ingels A, Oudard S, Moatti A (2017) Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res 23:4416–4428

[76] Glažar P, Papavasileiou P, Rajewsky N (2014) circBase: a database for circular RNAs. RNA 20:1666–1670

[77] Gong Y, Mao J, Wu D, Wang X, Li L, Zhu L, Song R (2018) CircZEB1.33 promotes the proliferation of human HCC by sponging miR-200a-3p and upregulating CDK6. Cancer Cell Int 18:116

[78] Gu C, Zhou N, Wang Z, Li G, Kou Y, Yu S, Feng Y, Chen L, Yang J, Tian F (2018) circGprc5a promoted bladder oncogenesis and metastasis through Gprc5a-targeting peptide. Mol Ther Nucleic Acids 13:633–641

[79] Gu Y, Ke G, Wang L, Zhou E, Zhu K, Wei Y (2017) Altered expression profile of circular RNAs in the serum of patients with diabetic retinopathy revealed by microarray. Ophthalmic Res 58:176–184

[80] Guarnerio J, Bezzi M, Jeong J, Paffenholz SV, Berry K, Naldini MM, Lo-Coco F, Tay Y, Beck AH, Pandolfi P (2016) Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 165:289–302

[81] Gunsolus IL, Sweeney TE, Liesenfeld O, Ledeboer NA (2019) Diagnosing and managing sepsis by probing the host response to infection: advances, opportunities, and challenges. J Clin Microbiol 57:e00425–e1419

[82] Guo JU, Agarwal V, Guo H, Bartel DP (2014) Expanded identification and characterization of mammalian circular RNAs. Genome Biol 15:409

[83] Guo G, Wang H, Ye L, Shi X, Yan K, Lin K, Huang Q, Li B, Lin Q, Zhu L (2019) Hsa_circ_0000479 as a novel diagnostic biomarker of systemic lupus erythematosus. Front Immunol 10:2281

[84] Gupta RK, Turner CT, Venturini C, Esmail H, Rangaka MX, Copas A, Lipman M, Abubakar I, Noursadeghi M, Gupta RK (2020) Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis. Lancet Respir Med 8:395–406

[85] Han D, Li R, Shi J, Tan P, Zhang R, Li J (2020a) Liquid biopsy for infectious diseases: a focus on microbial cell-free DNA sequencing. Theranostics 10:5501–5513

[86] Han J, Zhang L, Hu L, Yu H, Xu F, Yang B, Zhang R, Zhang Y, An Y (2020b) Circular RNA-expression profiling reveals a potential role of hsa_circ_0097435 in heart failure via sponging multiple microRNAs. Front Genet 11:212

[87] Han L, Zhang X, Wang A, Ji Y, Cao X, Qin Q, Yu T, Yin L, Huang H (2020c) A dual-circular RNA signature as a non-invasive diagnostic biomarker for gastric cancer. Front Oncol 10:184

[88] Hanan M, Simchovitz A, Yayon N, Vaknine S, Cohen-Fultheim R, Karmon M, Madrer N, Rohrlich TM, Maman M, Bennett ER (2020) A Parkinson’s disease circRNAs resource reveals a link between circSLC8A1 and oxidative stress. EMBO Mol Med 12(9): e11942

[89] Hang D, Zhou J, Qin N, Zhou W, Ma H, Jin G, Hu Z, Dai J, Shen H (2018) A novel plasma circular RNA circFARSA is a potential biomarker for non-small cell lung cancer. Cancer Med 7:2783–2791

[90] Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384–388

[91] Hardwick SA, Deveson IW, Mercer TR (2017) Reference standards for next-generation sequencing. Nat Rev Genet 18(8):473–484

[92] He F, Zhong X, Lin Z, Lin J, Qiu M, Li X, Hu Z (2020) Plasma exohsa_circRNA_0056616: A potential biomarker for lymph node metastasis in lung adenocarcinoma. J Cancer 11:4037–4046

[93] Heitzer E, Haque IS, Roberts CES, Speicher MR (2019) Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 20:71–88

[94] Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, Kohlmaier A, Herbst A, Northoff BH, Nicolaou A (2016) Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun 7:12429

[95] Hong DK, Blauwkamp TA, Kertesz M, Bercovici S, Truong C, Banaei N (2018) Liquid biopsy for infectious diseases: sequencing of cell-free plasma to detect pathogen DNA in patients with invasive fungal disease. Diagn Microbiol Infect Dis 92(3):210–213

[96] Hsu M-T, Coca-Prados M (1979) Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature 280:339–340

[97] Hu X, Wu D, He X, Zhao H, He Z, Lin J, Wang K, Wang W, Pan Z, Lin H (2019) circGSK3beta promotes metastasis in esophageal squamous cell carcinoma by augmenting beta-catenin signaling. Mol Cancer 18:160

[98] Hu Y, Zhu Y, Zhang W, Lang J, Ning L (2019) Utility of plasma circBNC2 as a diagnostic biomarker in epithelial ovarian cancer. Onco Targets Ther 12:9715–9723

[99] Hu ZQ, Zhou SL, Li J, Zhou ZJ, Wang PC, Xin HY, Mao L, Luo CB, Yu SY, Huang XW (2019) Circular RNA sequencing identifies circASAP1 as a key regulator in hepatocellular carcinoma metastasis. Hepatology. https://doi.org/10.1002/hep.31068

[100] Huang M, He YR, Liang LC, Huang Q, Zhu ZQ (2017a) Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer. World J Gastroenterol 23:6330–6338

[101] Huang R, Zhang Y, Han B, Bai Y, Zhou R, Gan G, Chao J, Hu G, Yao H (2017b) Circular RNA HIPK2 regulates astrocyte activation via cooperation of autophagy and ER stress by targeting MIR1242HG. Autophagy 13:1722–1741

[102] Huang Z, Su R, Deng Z, Xu J, Peng Y, Luo Q, Li J (2017c) Identification of differentially expressed circular RNAs in human monocyte derived macrophages response to Mycobacterium tuberculosis infection. Sci Rep 7:13673

[103] Huang Z, Su R, Qing C, Peng Y, Luo Q, Li J (2018a) Plasma circular RNAs hsa_circ_0001953 and hsa_circ_0009024 as diagnostic biomarkers for active tuberculosis. Front Microbiol 9:2010

[104] Huang Z, Su R, Yao F, Peng Y, Luo Q, Li J (2018b) Circulating circular RNAs hsa_circ_0001204 and hsa_circ_0001747 act as diagnostic biomarkers for active tuberculosis detection. Int J Clin Exp Pathol 11:586–594

[105] Huang Z-K, Yao F-Y, Xu J-Q, Deng Z, Su R-G, Peng Y-P, Luo Q, Li J-M (2018c) Microarray expression profile of circular RNAs in peripheral blood mononuclear cells from active tuberculosis patients. Cell Physiol Biochem 45:1230–1240

[106] Huang A, Zheng H, Wu Z, Chen M, Huang Y (2020a) Circular RNA–protein interactions: functions, mechanisms, and identification. Theranostics 10:3503–3517

[107] Huang XY, Huang ZL, Huang J, Xu B, Huang XY, Xu YH, Zhou J, Tang ZY (2020b) Exosomal circRNA-100338 promotes hepatocellular carcinoma metastasis via enhancing invasiveness and angiogenesis. J Exp Clin Cancer Res 39:20

[108] Iparraguirre L, Muñoz-Culla M, Prada-Luengo I, Castillo-Triviño T, Olascoaga J, Otaegui D (2017) Circular RNA profiling reveals that circular RNAs from ANXA2 can be used as new biomarkers for multiple sclerosis. Hum Mol Genet 26:3564–3572

[109] Ivanov A, Memczak S, Wyler E, Torti F, Porath HT, Orejuela MR, Piechotta M, Levanon EY, Landthaler M, Dieterich C (2014) Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep 10:170–177

[110] Jeck WR, Sharpless NE (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32:453–461

[111] Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19:141–157

[112] Ji P, Wu W, Chen S, Zheng Y, Zhou L, Zhang J, Cheng H, Yan J, Zhang S, Yang P (2019) Expanded expression landscape and prioritization of circular RNAs in mammals. Cell Rep 26:3444–3460.e3445

[113] Jiang M, Lash GE, Zhao X, Long Y, Guo C, Yang H (2018) CircRNA0004904, circRNA-0001855, and PAPP-A: potential novel biomarkers for the prediction of preeclampsia. Cell Physiol Biochem 46:2576–2586

[114] Joosse SA, Pantel K (2015) Tumor-educated platelets as liquid biopsy in cancer patients. Cancer Cell 28:552–554

[115] Jost I, Shalamova LA, Gerresheim GK, Niepmann M, Bindereif A, Rossbach O (2018) Functional sequestration of microRNA-122 from Hepatitis C Virus by circular RNA sponges. RNA Biol 15(8):1–8

[116] Karczewski KJ, Snyder MP (2018) Integrative omics for health and disease. Nat Rev Genet 19:299–310

[117] Kelly S, Greenman C, Cook PR, Papantonis A (2015) Exon skipping is correlated with exon circularization. J Mol Biol 427:2414–2417

[118] Khan M, Reckman YJ, Aufiero S, van den Hoogenhof M, van der Made I, Beqqali A, Koolbergen DR, Rasmussen TB, van der Velden J, Creemers EE (2016) RBM20 regulates circular RNA production from the Titin gene. Circ Res 119:996–1003

[119] Kleaveland B, Shi CY, Stefano J, Bartel DP (2018) A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174(2):350–362

[120] Kölling M, Haddad G, Wegmann U, Kistler A, Bosakova A, Seeger H, Hübel K, Haller H, Mueller T, Wüthrich RP (2019) Circular RNAs in urine of kidney transplant patients with acute T cellmediated allograft rejection. Clin Chem 65:1287–1294

[121] Kong S, Yang Q, Tang C, Wang T, Shen X, Ju S (2019) Identification of hsa_circ_0001821 as a novel diagnostic biomarker in gastric cancer via comprehensive circular RNA profiling. Front Genet 10:878

[122] Kossenkov AV, Qureshi R, Dawany NB, Wickramasinghe J, Liu Q, Majumdar SR, Chang C, Widura S, Kumar T, Horng W-H (2018) A gene expression classifier from whole blood distinguishes benign from malignant lung nodules detected by lowdose CT. Cancer Res 79:263–273

[123] Kramer MC, Liang D, Tatomer DC, Gold B, March ZM, Cherry S, Wilusz JE (2015) Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev 29(20):2168–2182

[124] Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20:1–17

[125] Kumar L, Shamsuzzama HR, Haque R, Baghel T, Nazir A (2017) Circular RNAs: the emerging class of non-coding RNAs and their potential role in human neurodegenerative diseases. Mol Neurobiol 54:7224–7234

[126] Kwapisz D (2017) The first liquid biopsy test approved. Is it a new era of mutation testing for non-small cell lung cancer? Ann Transl Med 5:46

[127] Lam WKJ, Lo YMD (2019) Circular RNAs as urinary biomarkers. Clin Chem 65:1196–1198

[128] Lamb YN, Dhillon S (2017) Epi proColon® 2.0 CE: a blood-based screening test for colorectal cancer. Mol Diagn Ther 21:225–232

[129] Lasda E, Parker R (2016) Circular RNAs co-precipitate with extracellular vesicles: a possible mechanism for circRNA clearance. PLoS ONE 11:e0148407

[130] Legnini I, Timoteo GD, Rossi F, Morlando M, Briganti F, Sthandier O, Fatica A, Santini T, Andronache A, Wade M (2017) CircZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell 66:22–37

[131] Lei B, Zhou J, Xuan X, Tian Z, Zhang M, Gao W, Lin Y, Ni B, Pang H, Fan W (2019) Circular RNA expression profiles of peripheral blood mononuclear cells in hepatocellular carcinoma patients by sequence analysis. Cancer Med 8:1423–1433

[132] Lesko LJ, Atkinson AJ (2001) Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annu Rev Pharmacol Toxicol 41:347–366

[133] Li P, Chen S, Chen H, Mo X, Li T, Shao Y, Xiao B, Guo J (2015a) Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta 444:132–136

[134] Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S (2015b) Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 25:981–984

[135] Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L (2015c) Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22:256–264

[136] Li M, Xie X, Zhou J, Sheng M, Yin X, Ko E-A, Zhou T, Gu W (2017a) Quantifying circular RNA expression from RNA-seq data using model-based framework. Bioinformatics 33(14):2131–2139

[137] Li S, Li Y, Chen B, Zhao J, Yu S, Tang Y, Zheng Q, Li Y, Wang P, He X (2017b) exoRBase: a database of circRNA, lncRNA and mRNA in human blood exosomes. Nucleic Acids Res 46:D106–D112

[138] Li W, Zhong C, Jiao J, Li P, Cui B, Ji C, Ma D (2017c) 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):597

[139] Li WH, Song YC, Zhang H, Zhou ZJ, Xie X, Zeng QN, Guo K, Wang T, Xia P, Chang DM (2017d) Decreased expression of hsa_circ_00001649 in gastric cancer and its clinical significance. Dis Markers 2017:4587698

[140] Li X, Liu C-X, Xue W, Zhang Y, Jiang S, Yin Q-F, Wei J, Yao R-W, Yang L, Chen L-L (2017e) Coordinated circRNA biogenesis and function with NF90/NF110 in viral infection. Mol Cell 67:214–227. e217

[141] Li J, Li Z, Jiang P, Peng M, Zhang X, Chen K, Liu H, Bi H, Liu X, Li X (2018a) Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res 37:177

[142] Li L, Li W, Chen N, Zhao H, Xu G, Zhao Y, Pan X, Zhang X, Zhou L, Yu D (2018b) FLI1 exonic circular RNAs as a novel oncogenic driver to promote tumor metastasis in small cell lung cancer. Clin Cancer Res 25:1302–1317

[143] Li T, Shao Y, Fu L, Xie Y, Zhu L, Sun W, Yu R, Xiao B, Guo J (2018c) Plasma circular RNA profiling of patients with gastric cancer and their droplet digital RT-PCR detection. J Mol Med (Berl) 96:85–96

[144] Li X, Yang L, Chen L-L (2018d) The biogenesis, functions, and challenges of circular RNAs. Mol Cell 71:428–442

[145] Li Z, Yanfang W, Li J, Jiang P, Peng T, Chen K, Zhao X, Zhang Y, Zhen P, Zhu J (2018e) Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/ MET pathway in pancreatic cancer. Cancer Lett 432:237–250

[146] Li Q, Wang Y, Wu S, Zhou Z, Ding X, Shi R, Thorne RF, Zhang XD, Hu W, Wu M (2019a) CircACC1 regulates assembly and activation of AMPK complex under metabolic stress. Cell Metab 30:157–173

[147] Li S, Zhang J, Tan X, Deng J, Li Y, Piao Y, Li C, Yang W, Mo W, Sun J (2019b) Microarray expression profile of circular RNAs and mRNAs in children with systemic lupus erythematosus. Clin Rheumatol 38:1339–1350

[148] Li XN, Wang ZJ, Ye CX, Zhao BC, Huang XX, Yang L (2019c) Circular RNA circVAPA is up-regulated and exerts oncogenic properties by sponging miR-101 in colorectal cancer. Biomed Pharmacother 112:108611

[149] Li Y, Zhao J, Yu S, Wang Z, He X, Su Y, Guo T, Sheng H, Chen J, Zheng Q (2019d) Extracellular vesicles long RNA sequencing reveals abundant mRNA, circRNA, and lncRNA in human blood as potential biomarkers for cancer diagnosis. Clin Chem 65:798–808

[150] Li Z, Zhou Y, Yang G, He S, Qiu X, Zhang L, Deng Q, Zheng F (2019e) Using circular RNA SMARCA5 as a potential novel biomarker for hepatocellular carcinoma. Clin Chim Acta 492:37–44

[151] Li Z, Zhu X, Huang S (2020) Extracellular vesicle long non-coding RNAs and circular RNAs: biology, functions and applications in cancer. Cancer Lett 489:111–120

[152] Liang D, Wilusz JE (2014) Short intronic repeat sequences facilitate circular RNA production. Genes Dev 28:2233–2247

[153] Liang D, Tatomer DC, Luo Z, Wu H, Yang L, Chen L-L, Cherry S, Wilusz JE (2017) The output of protein-coding genes shifts to circular RNAs when the pre-mRNA processing machinery is limiting. Mol Cell 68:940–954.e943

[154] Liang B, Li M, Deng Q, Wang C, Rong J, He S, Xiang Y, Zheng F (2020) CircRNA ZNF609 in peripheral blood leukocytes acts as a protective factor and a potential biomarker for coronary artery disease. Ann Transl Med 8:741

[155] Lin J, Cai D, Li W, Yu T, Mao H, Jiang S, Xiao B (2019) Plasma circular RNA panel acts as a novel diagnostic biomarker for colorectal cancer. Clin Biochem 74:60–68

[156] Liu C-X, Li X, Nan F, Jiang S, Gao X, Guo S-K, Xue W, Cui Y, Dong K, Ding H (2019a) Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell 177 (4):865–880

[157] Liu XX, Yang YE, Liu X, Zhang MY, Li R, Yin YH, Qu YQ (2019b) A two-circular RNA signature as a noninvasive diagnostic biomarker for lung adenocarcinoma. J Transl Med 17:50

[158] Liu YT, Han XH, Xing PY, Hu XS, Hao XZ, Wang Y, Li JL, Zhang ZS, Yang ZH, Shi YK (2019c) Circular RNA profiling identified as a biomarker for predicting the efficacy of Gefitinib therapy for nonsmall cell lung cancer. J Thorac Dis 11:1779–1787

[159] Liu H, Lu G, Wang W, Jiang X, Gu S, Wang J, Yan X, He F, Wang J (2020) A panel of circRNAs in the serum serves as biomarkers for Mycobacterium tuberculosis Infection. Front Microbiol 11:1215

[160] Loon EV, Gazut S, Yazdani S, Lerut E, de Loor H, Coemans M, Noël L-H, Thorrez L, Lommel LV, Schuit F (2019) Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: a multicentre, prospective study. EBioMedicine 46:463–472

[161] Lu J, Zhang PY, Xie JW, Wang JB, Lin JX, Chen QY, Cao LL, Huang CM, Li P, Zheng CH (2019a) hsa_circ_0000467 promotes cancer progression and serves as a diagnostic and prognostic biomarker for gastric cancer. J Clin Lab Anal 33:e22726

[162] Lu J, Zhang PY, Xie JW, Wang JB, Lin JX, Chen QY, Cao LL, Li P, Zheng CH, Huang CM (2019b) Circular RNA hsa_circ_0006848 related to ribosomal protein L6 acts as a novel biomarker for early gastric cancer. Dis Markers 2019:3863458

[163] Lu X, Song M, Wang F (2019c) Circulating circular RNAs as biomarkers of cancer. Non-coding RNA Investig 3:8

[164] Lukiw WJ (2013) Circular RNA (circRNA) in Alzheimer’s disease (AD). Front Genet 4:307

[165] Luo Q, Zhang L, Li X, Fu B, Deng Z, Qing C, Su R, Xu J, Guo Y, Huang Z (2018) Identification of circular RNAs hsa_circ_0044235 in peripheral blood as novel biomarkers for rheumatoid arthritis. Clin Exp Immunol 194:118–124

[166] Luo Q, Zhang L, Li X, Fu B, Guo Y, Huang Z, Li J (2019) Identification of circular RNAs hsa_circ_0044235 and hsa_circ_0068367 as novel biomarkers for systemic lupus erythematosus. Int J Mol Med 44:1462–1472

[167] Luo H, Zhao Q, Wei W, Zheng L, Yi S, Li G, Wang W, Sheng H, Pu H, Mo H (2020a) Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med 12:eaax7533

[168] Luo HL, Peng Y, Luo H, Zhang JA, Liu GB, Xu H, Huang GX, Sun YF, Huang J, Zheng BY (2020b) Circular RNA hsa_circ_0001380 in peripheral blood as a potential diagnostic biomarker for active pulmonary tuberculosis. Mol Med Rep 21:1890–1896

[169] Luo Y-H, Yang Y-P, Chien C-S, Yarmishyn AA, Ishola AA, Chien Y, Chen Y-M, Huang T-W, Lee K-Y, Huang W-C (2020c) Plasma level of circular RNA hsa_circ_0000190 correlates with tumor progression and poor treatment response in advanced lung cancers. Cancers 12:1740

[170] Ma J, Qi G, Li L (2020) A novel serum exosomes-based biomarker hsa_circ_0002130 facilitates osimertinib-resistance in non-small cell lung cancer by sponging miR-498. Onco Targets Ther 13:5293–5307

[171] Maas SLN, Breakefield XO, Weaver AM (2017) Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol 27:172–188

[172] Maass PG, Glažar P, Memczak S, Dittmar G, Hollfinger I, Schreyer L, Sauer AV, Toka O, Aiuti A, Luft FC (2017) A map of human circular RNAs in clinically relevant tissues. J Mol Med (Berl) 95:1179–1189

[173] MacLean E, Broger T, Yerlikaya S, Fernandez-Carballo BL, Pai M, Denkinger CM (2019) A systematic review of biomarkers to detect active tuberculosis. Nat Microbiol 4:748–758

[174] Marshall K, Mohr S, Khettabi F, Nossova N, Chao S, Bao W, Ma J, Li XJ, Liew CC (2010) A blood-based biomarker panel for stratifying current risk for colorectal cancer. Int J Cancer 126:1177–1186

[175] Mattox AK, Bettegowda C, Zhou S, Papadopoulos N, Kinzler KW, Vogelstein B (2019) Applications of liquid biopsies for cancer. Sci Transl Med 11:eaay1984

[176] Max KEA, Bertram K, Akat K, Bogardus KA, Li J, Morozov P, BenDov IZ, Li X, Weiss ZR, Azizian A (2018) Human plasma and serum extracellular small RNA reference profiles and their clinical utility. Proc Natl Acad Sci USA 115:201714397

[177] Mayhew MB, Buturovic L, Luethy R, Midic U, Moore AR, Roque JA, Shaller BD, Asuni T, Rawling D, Remmel M (2020) A generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections. Nat Commun 11:1177

[178] Mei M, Wang Y, Wang Q, Liu Y, Song W, Zhang M (2019) CircCDYL serves as a new biomarker in Mantle cell lymphoma and promotes cell proliferation. Cancer Manag Res 11:10215–10221

[179] Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338

[180] Memczak S, Papavasileiou P, Peters O, Rajewsky N (2015) Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS ONE 10: e0141214

[181] Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, Wu M (2017) CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer 16:94

[182] Miao Q, Zhong Z, Jiang Z, Lin Y, Ni B, Yang W, Tang J (2019) RNAseq of circular RNAs identified circPTPN22 as a potential new activity indicator in systemic lupus erythematosus. Lupus 28:520–528

[183] Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, PogosovaAgadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105:10513–10518

[184] Ng WL, Marinov GK, Liau ES, Lam YL, Lim Y-Y, Ea C-K (2016) Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway. RNA Biol 13:861–871

[185] Nicolet BP, Engels S, Aglialoro F, van den Akker E, von Lindern M, Wolkers MC (2018) Circular RNA expression in human hematopoietic cells is widespread and cell-type specific. Nucleic Acids Res 46:8168–8180

[186] Ouyang Q, Huang Q, Jiang Z, Zhao J, Shi GP, Yang M (2018) Using plasma circRNA_002453 as a novel biomarker in the diagnosis of lupus nephritis. Mol Immunol 101:531–538

[187] Ouyang Q, Wu J, Jiang Z, Zhao J, Wang R, Lou A, Zhu D, Shi GP, Yang M (2017) Microarray expression profile of circular RNAs in peripheral blood mononuclear cells from rheumatoid arthritis patients. Cell Physiol Biochem 42:651–659

[188] Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L, Hanan M, Wyler E, Perez-Hernandez D, Ramberger E (2017) Translation of circRNAs. Mol Cell 66:9–21

[189] Pan B, Qin J, Liu X, He B, Wang X, Pan Y, Sun H, Xu T, Xu M, Chen X (2019) Identification of serum exosomal hsa-circ-0004771 as a novel diagnostic biomarker of colorectal cancer. Front Genet 10:1096

[190] Pardini B, Sabo A, Birolo G, Calin G (2019) Noncoding RNAs in extracellular fluids as cancer biomarkers: the new frontier of liquid biopsies. Cancers 11:1170

[191] Park O, Ha H, Lee Y, Boo S, Kwon D, Song H, Kim Y (2019) Endoribonucleolytic cleavage of m6A-containing RNAs by RNase P/MRP complex. Mol Cell 74(3):494–507

[192] Peng YK, Pu K, Su HX, Zhang J, Zheng Y, Ji R, Guo QH, Wang YP, Guan QL, Zhou YN (2020) Circular RNA hsa_circ_0010882 promotes the progression of gastric cancer via regulation of the PI3K/Akt/mTOR signaling pathway. Eur Rev Med Pharmacol Sci 24:1142–1151

[193] Ping L, Jian-Jun C, Chu-Shu L, Guang-Hua L, Ming Z (2019) High circ_100053 predicts a poor outcome for chronic myeloid leukemia and is involved in imatinib resistance. Oncol Res. https://doi.org/10.3727/096504018x15412701483326

[194] Piwecka M, Glažar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, Filipchyk A, Klironomos F, Cerda Jara CA, Fenske P (2017) Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357: eaam8526

[195] Powers KA, Ghani AC, Miller WC, Hoffman IF, Pettifor AE, Kamanga G, Martinson FE, Cohen MS (2011) The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study. Lancet 378:256–268

[196] Preußer C, Hung L-H, Schneider T, Schreiner S, Hardt M, Moebus A, Santoso S, Bindereif A (2018) Selective release of circRNAs in platelet-derived extracellular vesicles. J Extracell Vesicles 7:1424473

[197] Qian Z, Liu H, Li M, Shi J, Li N, Zhang Y, Zhang X, Lv J, Xie X, Bai Y (2018) Potential diagnostic power of blood circular RNA expression in active pulmonary tuberculosis. EBioMedicine 27:18–26

[198] Qian Z, Lv J, Kelly GT, Wang H, Zhang X, Gu W, Yin X, Wang T, Zhou T (2016) Expression of nuclear factor, erythroid 2-like 2-mediated genes differentiates tuberculosis. Tuberculosis 99:56–62

[199] Qiao GL, Chen L, Jiang WH, Yang C, Yang CM, Song LN, Chen Y, Yan HL, Ma LJ (2019) Hsa_circ_0003998 may be used as a new biomarker for the diagnosis and prognosis of hepatocellular carcinoma. Onco Targets Ther 12:5849–5860

[200] Ramilo O, Mejias A (2017) Host transcriptomics for diagnosis of infectious diseases: one step closer to clinical application. Eur Respir J 49:1700993

[201] Ravnik-Glavač M, Glavač D (2020) Circulating RNAs as potential biomarkers in amyotrophic lateral sclerosis. Int J Mol Sci 21:1714

[202] Revenfeld ALS, Bæk R, Nielsen MH, Stensballe A, Varming K, Jørgensen M (2014) Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. Clin Ther 36:830–846

[203] Richey LE, Halperin J (2013) Acute human immunodeficiency virus infection. Am J Med Sci 345:136–142

[204] Rong D, Lu C, Zhang B, Fu K, Zhao S, Tang W, Cao H (2019) CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p. Mol Cancer 18:25

[205] Rose S, Contrepois K, Moneghetti KJ, Zhou W, Mishra T, Mataraso S, Dagan-Rosenfeld O, Ganz AB, Dunn J, Hornburg D (2019) A longitudinal big data approach for precision health. Nat Med 25:792–804

[206] Ross RW, Galsky MD, Scher HI, Magidson J, Wassmann K, Lee G-S, Katz L, Subudhi SK, Anand A, Fleisher M (2012) A whole-blood RNA transcript-based prognostic model in men with castration-resistant prostate cancer: a prospective study. Lancet Oncol 13:1105–1113

[207] Rubis G, Krishnan S, Bebawy M (2019) Liquid biopsies in cancer diagnosis, monitoring, and prognosis. Trends Pharmacol Sci 40:172–186

[208] Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R (2015) Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 58:870–885

[209] Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO (2013) Celltype specific features of circular RNA expression. PLoS Genet 9 (9):e1003777

[210] Salzman J, Gawad C, Wang P, Lacayo N, Brown PO (2012) Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS ONE.

[211] Sambarey A, Devaprasad A, Mohan A, Ahmed A, Nayak S, Swaminathan S, D’Souza G, Jesuraj A, Dhar C, Babu S (2017) Unbiased identification of blood-based biomarkers for pulmonary tuberculosis by modeling and mining molecular interaction networks. EBioMedicine 15:112–126

[212] Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK (1976) Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci USA 73:3852–3856

[213] Schnell A, Schmidl C, Herr W, Siska PJ (2018) The peripheral and intratumoral immune cell landscape in cancer patients: a proxy for tumor biology and a tool for outcome prediction. Biomedicines 6:25

[214] Shaked Y (2019) The pro-tumorigenic host response to cancer therapies. Nat Rev Cancer 19:667–685

[215] Shang A, Gu C, Wang W, Wang X, Sun J, Zeng B, Chen C, Chang W, Ping Y, Ji P (2020) Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3pTGF-β1 axis. Mol Cancer 19:117

[216] Shang Q, Yang Z, Jia R, Ge S (2019) The novel roles of circRNAs in human cancer. Mol Cancer 18:6

[217] Shao Y, Tao X, Lu R, Zhang H, Ge J, Xiao B, Ye G, Guo J (2020) Hsa_circ_0065149 is an indicator for early gastric cancer screening and prognosis prediction. Pathol Oncol Res 26:1475–1482

[218] Sheng R, Li X, Wang Z, Wang X (2020) Circular RNAs and their emerging roles as diagnostic and prognostic biomarkers in ovarian cancer. Cancer Lett 473:139–147

[219] Shi L, Tao C, Tang Y, Xia Y, Li X, Wang X (2020) Hypoxia-induced hsa_circ_0000826 is linked to liver metastasis of colorectal cancer. J Clin Lab Anal 34(9):e23405

[220] Showe MK, Vachani A, Kossenkov AV, Yousef M, Nichols C, Nikonova EV, Chang C, Kucharczuk J, Tran B, Wakeam E (2009) Gene expression profiles in peripheral blood mononuclear cells can distinguish patients with non-small cell lung cancer from patients with nonmalignant lung disease. Cancer Res 69:9202–9210

[221] Shuai M, Hong J, Huang D, Zhang X, Tian Y (2018) Upregulation of circRNA_0000285 serves as a prognostic biomarker for nasopharyngeal carcinoma and is involved in radiosensitivity. Oncol Lett 16:6495–6501

[222] Siravegna G, Marsoni S, Siena S, Bardelli A (2017) Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 14:531–548

[223] Smid M, Wilting SM, Uhr K, Rodríguez-González GF, de Weerd V, van der Smissen WJC, van der Vlugt-Daane M, van Galen A, Nik-Zainal S, Butler A (2019) The circular RNome of primary breast cancer. Genome Res 29:356–366

[224] Sole C, Arnaiz E, Manterola L, Otaegui D, Lawrie CH (2019) The circulating transcriptome as a source of cancer liquid biopsy biomarkers. Semin Cancer Biol 58:100–108

[225] Song R, Bai Y, Li X, Zhu J, Zhang H, Shi Y, Li K, Wang B, Zhang H, Yang Y (2020) Plasma circular RNA DYM related to major depressive disorder and rapid antidepressant effect treated by visual cortical repetitive transcranial magnetic stimulation. J Affect Disord 274:486–493

[226] Sonnenschein K, Wilczek A, de Gonzalo-Calvo D, Pfanne A, Derda A, Zwadlo C, Bavendiek U, Bauersachs J, Fiedler J, Thum T (2019) Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy. Sci Rep 9:20350

[227] Stark R, Grzelak M, Hadfield J (2019) RNA sequencing: the teenage years. Nat Rev Genet 20:1–26

[228] Starke S, Jost I, Rossbach O, Schneider T, Schreiner S, Hung L-H, Bindereif A (2014) Exon circularization requires canonical splice signals. Cell Rep 10:103–111

[229] Su M, Xiao Y, Ma J, Tang Y, Tian B, Zhang Y, Li X, Wu Z, Yang D, Zhou Y (2019) Circular RNAs in cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers. Mol Cancer 18:90

[230] Sun J-Y, Shi Y, Cai X-Y, Liu J (2020) Potential diagnostic and therapeutic value of circular RNAs in cardiovascular diseases. Cell Signal 71:109604

[231] Sun X-H, Wang Y-T, Li G-F, Zhang N, Fan L (2020) Serum-derived three-circRNA signature as a diagnostic biomarker for hepatocellular carcinoma. Cancer Cell Int 20:226

[232] Sun Y, Jiang X, Lv Y, Liang X, Zhao B, Bian W, Zhang D, Jiang J, Zhang C (2020) Circular RNA expression profiles in plasma from patients with heart failure related to platelet activity. Biomolecules 10(2):187

[233] Surinova S, Radová L, Choi M, Srovnal J, Brenner H, Vitek O, Hajdúch M, Aebersold R (2015) Non-invasive prognostic protein biomarker signatures associated with colorectal cancer. EMBO Mol Med 7:1153–1165

[234] Sweeney TE, Perumal TM, Henao R, Nichols M, Howrylak JA, Choi AM, Bermejo-Martin JFF, Almansa R, Tamayo E, Davenport EE (2018) A community approach to mortality prediction in sepsis via gene expression analysis. Nat Commun 9:694

[235] Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, Parast MM, Murry CE, Laurent LC, Salzman J (2015) Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biol 16:126

[236] Szabo L, Salzman J (2016) Detecting circular RNAs: bioinformatic and experimental challenges. Nat Rev Genet 17:679–692

[237] Tan S, Gou Q, Pu W, Guo C, Yang Y, Wu K, Liu Y, Liu L, Wei Y-Q, Peng Y (2018) Circular RNA F-circEA produced from EML4-ALK fusion gene as a novel liquid biopsy biomarker for non-small cell lung cancer. Cell Res 28:693–695

[238] Tang W, Fu K, Sun H, Rong D, Wang H, Cao H (2018) CircRNA microarray profiling identifies a novel circulating biomarker for detection of gastric cancer. Mol Cancer 17:137

[239] Tang X, Liu S, Ding Y, Guo C, Guo J, Hua K, Qiu J (2020) Serum circular FoxO3a serves as a novel prognostic biomarker in squamous cervical cancer. Cancer Manag Res 12:2531–2540

[240] Tao X, Shao Y, Lu R, Ye Q, Xiao B, Ye G, Guo J (2020) Clinical significance of hsa_circ_0000419 in gastric cancer screening and prognosis estimation. Pathol Res Pract 216:152763

[241] Teng L, Chen Y, Chen H, He X, Wang J, Peng Y, Duan H, Li H, Lin D, Shao B (2017) Circular RNA hsa_circ_0021001 in peripheral blood: a potential novel biomarker in the screening of intracranial aneurysm. Oncotarget 8:107125–107133

[242] Torrano V, Royo F, Peinado H, Loizaga-Iriarte A, Unda M, FalcónPerez JM, Carracedo A (2016) Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer. Curr Opin Pharmacol 29:47–53

[243] Tsalik EL, Henao R, Nichols M, Burke T, Ko ER, McClain MT, Hudson LL, Mazur A, Freeman DH, Veldman T (2016) Host gene expression classifiers diagnose acute respiratory illness etiology. Sci Transl Med 8:322ra311

[244] Turchinovich A, Weiz L, Langheinz A, Burwinkel B (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39:7223–7233

[245] Valk PJM, Verhaak RGW, Beijen MA, Erpelinck CAJ, van DoornKhosrovani SBvW, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Löwenberg B (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350:1617–1628

[246] van Heesch S, Witte F, Schneider-Lunitz V, Schulz JF, Adami E, Faber AB, Kirchner M, Maatz H, Blachut S, Sandmann C-L (2019) The translational landscape of the human heart. Cell 178 (1):242–260

[247] Vargas AJ, Harris CC (2016) Biomarker development in the precision medicine era: lung cancer as a case study. Nat Rev Cancer 16:525–537

[248] Vargas J, Lima JA, Kraus WE, Douglas PS, Rosenberg S (2013) Use of the Corus® CAD gene expression test for assessment of obstructive coronary artery disease likelihood in symptomatic non-diabetic patients. PLoS Curr.

[249] Vausort M, Salgado-Somoza A, Zhang L, Leszek P, Scholz M, Teren A, Burkhardt R, Thiery J, Wagner DR, Devaux Y (2016) Myocardial infarction-associated circular RNA predicting left ventricular dysfunction. J Am Coll Cardiol 68:1247–1248

[250] Venø MT, Hansen TB, Venø ST, Clausen BH, Grebing M, Finsen B, Holm IE, Kjems J (2015) Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol 16:245

[251] Vicens Q, Westhof E (2014) Biogenesis of circular RNAs. Cell 159:13–14

[252] Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu Y-M, Dhanasekaran SM, Engelke CG, Cao X (2019) The landscape of circular RNA in cancer. Cell 176:869–881.e813

[253] Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N (2017) Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 17:223–238

[254] Wang Y, Wang Z (2015) Efficient backsplicing produces translatable circular mRNAs. RNA 21:172–179

[255] Wang PL, Bao Y, Yee M-C, Barrett SP, Hogan GJ, Olsen MN, Dinneny JR, Brown PO, Salzman J (2014) Circular RNA is expressed across the eukaryotic tree of life. PLoS ONE 9(6): e90859

[256] Wang YM, Huang LM, Li DR, Shao JH, Xiong SL, Wang CM, Lu SM (2017a) Hsa_circ_0101996 combined with hsa_circ_0101119 in peripheral whole blood can serve as the potential biomarkers for human cervical squamous cell carcinoma. Int J Clin Exp Pathol 10:11924–11931

[257] Wang Z-Y, Guo Z-D, Li J-M, Zhao Z-Z, Fu Y-Y, Zhang C-M, Zhang Y, Liu L-N, Qian J, Liu L-N (2017b) Genome-wide search for competing endogenous RNAs responsible for the effects induced by Ebola virus replication and transcription using a trVLP system. Front Cell Infect Microbiol 7:479

[258] Wang L, Shen C, Wang Y, Zou T, Zhu H, Lu X, Li L, Yang B, Chen J, Chen S (2019a) Identification of circular RNA hsa_circ_0001879 and hsa_circ_0004104 as novel biomarkers for coronary artery disease. Atherosclerosis 286:88–96

[259] Wang Q, Zhang Q, Sun H, Tang W, Yang L, Xu Z, Liu Z, Jin H, Cao X (2019b) Circ-TTC17 promotes proliferation and migration of esophageal squamous cell carcinoma. Dig Dis Sci 64:751–758

[260] Wang W, Dong R, Guo Y, He J, Shao C, Yi P, Yu F, Gu D, Zheng J (2019c) CircMTO1 inhibits liver fibrosis via regulation of miR-175p and Smad7. J Cell Mol Med 23:5486–5496

[261] Wang W, Wang J, Zhang X, Liu G (2019d) Serum circSETDB1 is a promising biomarker for predicting response to platinum-taxanecombined chemotherapy and relapse in high-grade serous ovarian cancer. Onco Targets Ther 12:7451–7457

[262] Wang Y, Liu J, Ma J, Sun T, Zhou Q, Wang W, Wang G, Wu P, Wang H, Jiang L (2019e) Exosomal circRNAs: biogenesis, effect and application in human diseases. Mol Cancer 18:116

[263] Wang Y, Wu C, Zhang F, Zhang Y, Ren Z, Lammi MJ, Guo X (2019f) Screening for differentially expressed circular RNAs in the cartilage of osteoarthritis patients for their diagnostic value. Genet Test Mol Biomark 23:706–716

[264] Wang J, Kong J, Nie Z, Chen D, Qiang J, Gao W, Chen X (2020a) Circular RNA hsa_circ_0066755 as an oncogene via sponging miR-651 and as a promising diagnostic biomarker for nasopharyngeal carcinoma. Int J Med Sci 17:1499–1507

[265] Wang J, Zhao X, Wang Y, Ren F, Sun D, Yan Y, Kong X, Bu J, Liu M, Xu S (2020b) CircRNA-002178 act as a ceRNA to promote PDL1/ PD1 expression in lung adenocarcinoma. Cell Death Dis 11:32

[266] Wang Q, Liu H, Liu Z, Yang L, Zhou J, Cao X, Sun H (2020c) CircSLC7A5, a potential prognostic circulating biomarker for detection of ESCC. Cancer Genet 240:33–39

[267] Wang W, Li Y, Li X, Liu B, Han S, Li X, Zhang B, Li J, Sun S (2020d) Circular RNA circ-FOXP1 induced by SOX9 promotes hepatocellular carcinoma progression via sponging miR-875-3p and miR-421. Biomed Pharmacother 121:109517

[268] Wang Y, Wu C, Zhang Y, Yang Y, Ren Z, Lammi MJ, Guo X (2020e) Screening for differentially expressed circRNA between KashinBeck disease and osteoarthritis patients based on circRNA chips. Clin Chim Acta 501:92–101

[269] Warsinske H, Vashisht R, Khatri P (2019) Host-response-based gene signatures for tuberculosis diagnosis: a systematic comparison of 16 signatures. PLoS Med 16:e1002786

[270] Weng W, Wei Q, Toden S, Yoshida K, Nagasaka T, Fujiwara T, Cai S, Qin H, Ma Y, Goel A (2017) Circular RNA ciRS-7—a promising prognostic biomarker and a potential therapeutic target in colorectal cancer. Clin Cancer Res 23:3918–3928

[271] Westholm JO, Miura P, Olson S, Shenker S, Joseph B, Sanfilippo P, Celniker SE, Graveley BR, Lai EC (2014) Genome-wide analysis of Drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep 9:1966–1980

[272] Wilusz JE (2015) Repetitive elements regulate circular RNA biogenesis. Mob Genet Elem 5:39–45

[273] Wu H, Yang L, Chen L-L (2017a) The diversity of long noncoding RNAs and their generation. Trends Genet 33:540–552

[274] Wu N, Jin L, Cai J (2017b) Profiling and bioinformatics analyses reveal differential circular RNA expression in hypertensive patients. Clin Exp Hypertens 39:454–459

[275] Wu J, Li J, Liu H, Yin J, Zhang M, Yu Z, Miao H (2019a) Circulating plasma circular RNAs as novel diagnostic biomarkers for congenital heart disease in children. J Clin Lab Anal 33:e22998

[276] Wu J, Zhou Q, Niu Y, Chen J, Zhu Y, Ye S, Xi Y, Wang F, Qiu H, Bu S (2019b) Aberrant expression of serum circANRIL and hsa_circ_0123996 in children with Kawasaki disease. J Clin Lab Anal 33:e22874

[277] Wu W, Ji P, Zhao F (2020a) CircAtlas: an integrated resource of one million highly accurate circular RNAs from 1070 vertebrate transcriptomes. Genome Biol 21:101

[278] Wu WP, Pan YH, Cai MY, Cen JM, Chen C, Zheng L, Liu X, Xiong XD (2020b) Plasma-derived exosomal circular RNA hsa_circ_0005540 as a novel diagnostic biomarker for coronary artery disease. Dis Markers 2020:3178642

[279] Wu Z, Sun H, Liu W, Zhu H, Fu J, Yang C, Fan L, Wang L, Liu Y, Xu W (2020c) Circ-RPL15: a plasma circular RNA as novel oncogenic driver to promote progression of chronic lymphocytic leukemia. Leukemia 34:919–923

[280] Xia X, Li X, Li F, Wu X, Zhang M, Zhou H, Huang N, Yang X, Xiao F, Liu D (2019) A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1. Mol Cancer 18:131

[281] Xiao M-S, Ai Y, Wilusz JE (2020) Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol 30(3):226–240

[282] Xie M, Yu T, Jing X, Ma L, Fan Y, Yang F, Ma P, Jiang H, Wu X, Shu Y (2020a) Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation. Mol Cancer 19:112

[283] Xie R, Zhang Y, Zhang J, Li J, Zhou X (2020b) The role of circular RNAs in immune-related diseases. Front Immunol 11:545

[284] Xie Y, Li J, Li P, Li N, Zhang Y, Binang H, Zhao Y, Duan W, Chen Y, Wang Y (2020c) RNA-Seq profiling of serum exosomal circular RNAs reveals circ-PNN as a potential biomarker for human colorectal cancer. Front Oncol 10:982

[285] Xiong S, Peng H, Ding X, Wang X, Wang L, Wu C, Wang S, Xu H, Liu Y (2019) Circular RNA expression profiling and the potential role of hsa_circ_0089172 in Hashimoto’s thyroiditis via sponging miR125a-3p. Mol Ther Nucleic Acids 17:38–48

[286] Xu H, Guo S, Li W, Yu P (2015) The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells. Sci Rep 5:12453

[287] Xu H, Gong Z, Shen Y, Fang Y, Zhong S (2018a) Circular RNA expression in extracellular vesicles isolated from serum of patients with endometrial cancer. Epigenomics 10:187–197

[288] Xu Z, Li P, Fan L, Wu M (2018b) The potential role of circRNA in tumor immunity regulation and immunotherapy. Front Immunol 9:9

[289] Xu M, Xie F, Tang X, Wang T, Wang S (2020a) Insights into the role of circular RNA in macrophage activation and fibrosis disease. Pharmacol Res 156:104777

[290] Xu Y, Leng K, Yao Y, Kang P, Liao G, Han Y, Shi G, Ji D, Huang P, Zheng W (2020b) A novel circular RNA, circ-CCAC1, contributes to CCA progression, induces angiogenesis, and disrupts vascular endothelial barriers. Hepatology.

[291] Yan B, Zhang Y, Liang C, Liu B, Ding F, Wang Y, Zhu B, Zhao R, Yu X-Y, Li Y (2020) Stem cell-derived exosomes prevent pyroptosis and repair ischemic muscle injury through a novel exosome/circHIPK3/FOXO3a pathway. Theranostics 10:6728–6742

[292] Yang F, Liu DY, Guo JT, Ge N, Zhu P, Liu X, Wang S, Wang GX, Sun SY (2017a) Circular RNA circ-LDLRAD3 as a biomarker in diagnosis of pancreatic cancer. World J Gastroenterol 23:8345–8354

[293] Yang Q, Du WW, Wu N, Yang W, Awan F, Fang L, Ma J, Li X, Zeng Y, Yang Z (2017b) A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. Cell Death Differ 24 (9):1609–1620

[294] Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, Jin Y, Yang Y, Chen L, Wang Y (2017c) Extensive translation of circular RNAs driven by N⁽⁶⁾-methyladenosine. Cell Res 27:626–641

[295] Yang L, Fu J, Zhou Y (2018) Circular RNAs and their emerging roles in immune regulation. Front Immunol 9:2977

[296] Yang X, Li J, Wu Y, Ni B, Zhang B (2019) Aberrant dysregulated circular RNAs in the peripheral blood mononuclear cells of patients with rheumatoid arthritis revealed by RNA sequencing: novel diagnostic markers for RA. Scand J Clin Lab Investig 79:551–559

[297] Yao G, Niu W, Zhu X, He M, Kong L, Chen S, Zhang L, Cheng Z (2019) hsa_circRNA_104597: a novel potential diagnostic and therapeutic biomarker for schizophrenia. Biomark Med 13:331–340

[298] Ye DX, Wang SS, Huang Y, Chi P (2019) A 3-circular RNA signature as a noninvasive biomarker for diagnosis of colorectal cancer. Cancer Cell Int 19:276

[299] Yi Z, Gao K, Li R, Fu Y (2018) Dysregulated circRNAs in plasma from active tuberculosis patients. J Cell Mol Med 22:4076–4084

[300] Yin WB, Yan MG, Fang X, Guo JJ, Xiong W, Zhang RP (2018) Circulating circular RNA hsa_circ_0001785 acts as a diagnostic biomarker for breast cancer detection. Clin Chim Acta 487:363–368

[301] Yoshimoto R, Rahimi K, Hansen T, Kjems J, Mayeda A (2019) Biosynthesis of circular RNA ciRS-7/CDR1as is mediated by mammalian-wide interspersed repeats (MIRs). Biorxiv411231

[302] You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C, Quedenau C (2015) Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci 18:603–610

[303] Yu C-Y, Li T-C, Wu Y-Y, Yeh C-H, Chiang W, Chuang C-Y, Kuo H-C (2017) The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency. Nat Commun 8:1149

[304] Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580–584

[305] Zaas AK, Chen M, Varkey J, Veldman T, Hero AO, Lucas J, Huang Y, Turner R, Gilbert A, Lambkin-Williams R (2009) Gene expression signatures diagnose Influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 6:207–217

[306] Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, Mahomed H, Erasmus M, Whatney W, Hussey GD (2016) A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 387:2312–2322

[307] Zaporozhchenko IA, Ponomaryova AA, Rykova EY, Laktionov PP (2018) The potential of circulating cell-free RNA as a cancer biomarker: challenges and opportunities. Expert Rev Mol Diagn 18:133–145

[308] Zemmour H, Planer D, Magenheim J, Moss J, Neiman D, Gilon D, Korach A, Glaser B, Shemer R, Landesberg G (2018) Noninvasive detection of human cardiomyocyte death using methylation patterns of circulating DNA. Nat Commun 9:1443

[309] Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL (2013) Circular intronic long noncoding RNAs. Mol Cell 51:792–806

[310] Zhang X-O, Wang H-B, Zhang Y, Lu X, Chen L-L, Yang L (2014) Complementary sequence-mediated exon circularization. Cell 159:134–147

[311] Zhang YG, Yang HL, Long Y, Li WL (2016) Circular RNA in blood corpuscles combined with plasma protein factor for early prediction of pre-eclampsia. BJOG 123:2113–2118

[312] Zhang Y, Li J, Yu J, Liu H, Shen Z, Ye G, Mou T, Qi X, Li G (2017) Circular RNAs signature predicts the early recurrence of stage III gastric cancer after radical surgery. Oncotarget 8:22936–22943

[313] Zhang C, Wang X, Chen Y, Wu Z, Zhang C, Shi W (2018a) The down-regulation of hsa_circ_0012919, the sponge for miR-125a3p, contributes to DNA methylation of CD11a and CD70 in CD4 (+) T cells of systemic lupus erythematous. Clin Sci (Lond) 132:2285–2298

[314] Zhang H, Deng T, Ge S, Liu Y, Bai M, Zhu K, Fan Q, Li J, Ning T, Tian F (2018b) Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene 38:2844–2859

[315] Zhang J, Xu Y, Xu S, Liu Y, Yu L, Li Z, Xue X, Wang H (2018c) Plasma circular RNAs, hsa_circRNA_025016, predict postoperative atrial fibrillation after isolated off-pump coronary artery bypass grafting. J Am Heart Assoc 7:e006642

[316] Zhang M, Zhao K, Xu X, Yang Y, Yan S, Wei P, Liu H, Xu J, Xiao F, Zhou H (2018d) A peptide encoded by circular form of LINCPINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 9:4475

[317] Zhang MY, Wang JB, Zhu ZW, Li LJ, Liu RS, Yang XK, Leng RX, Li XM, Pan HF, Ye DQ (2018e) Differentially expressed circular RNAs in systemic lupus erythematosus and their clinical significance. Biomed Pharmacother 107:1720–1727

[318] Zhang W, Yang S, Liu Y, Wang Y, Lin T, Li Y, Zhang R (2018f) Hsa_circ_0007534 as a blood-based marker for the diagnosis of colorectal cancer and its prognostic value. Int J Clin Exp Pathol 11:1399–1406

[319] Zhang X, Xu Y, Qian Z, Zheng W, Wu Q, Chen Y, Zhu G, Liu Y, Bian Z, Xu W (2018g) CircRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma. Cell Death Dis 9:1091

[320] Zhang X, Zhou H, Jing W, Luo P, Qiu S, Liu X, Zhu M, Liang C, Yu M, Tu J (2018h) The circular RNA hsa_circ_0001445 regulates the proliferation and migration of hepatocellular carcinoma and may serve as a diagnostic biomarker. Dis Markers 2018:3073467

[321] Zhang Y, Zhang H, An M, Zhao B, Ding H, Zhang Z, He Y, Shang H, Han X (2018i) Crosstalk in competing endogenous RNA networks reveals new circular RNAs involved in the pathogenesis of early HIV infection. J Transl Med 16:332

[322] Zhang Z, Yang T, Xiao J (2018j) Circular RNAs: promising biomarkers for human diseases. EBioMedicine 34:267–274

[323] Zhang J, Li J, Saucier JB, Feng Y, Jiang Y, Sinson J, McCombs AK, Schmitt ES, Peacock S, Chen S (2019a) Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA. Nat Med 25:1–9

[324] Zhang Y, Chen Y, Yao H, Lie Z, Chen G, Tan H, Zhou Y (2019b) Elevated serum circ_0068481 levels as a potential diagnostic and prognostic indicator in idiopathic pulmonary arterial hypertension. Pulm Circ 9:2045894019888416

[325] Zhang P-F, Gao C, Huang X-Y, Lu J-C, Guo X-J, Shi G-M, Cai J-B, Ke A-W (2020a) Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer 19:110

[326] Zhang S, Song G, Yuan J, Qiao S, Xu S, Si Z, Yang Y, Xu X, Wang A (2020b) Circular RNA circ_0003204 inhibits proliferation, migration and tube formation of endothelial cell in atherosclerosis via miR-370-3p/TGFbetaR2/phosph-SMAD3 axis. J Biomed Sci 27:11

[327] Zhao Z, Li X, Gao C, Jian D, Hao P, Rao L, Li M (2017a) Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Sci Rep 7:39918

[328] Zhao Z, Li X, Jian D, Hao P, Rao L, Li M (2017b) Hsa_circ_0054633 in peripheral blood can be used as a diagnostic biomarker of prediabetes and type 2 diabetes mellitus. Acta Diabetol 54:237–245

[329] Zhao K, Zhao Q, Guo Z, Chen Z, Hu Y, Su J, Chen L, He Z, Cai X, Chen M (2018a) Hsa_circ_0001275: a potential novel diagnostic biomarker for postmenopausal osteoporosis. Cell Physiol Biochem 46:2508–2516

[330] Zhao Q, Chen S, Li T, Xiao B, Zhang X (2018b) Clinical values of circular RNA 0000181 in the screening of gastric cancer. J Clin Lab Anal 32:e22333

[331] Zhao T, Zheng Y, Hao D, Jin X, Luo Q, Guo Y, Li D, Xi W, Xu Y, Chen Y (2019) Blood circRNAs as biomarkers for the diagnosis of community-acquired pneumonia. J Cell Biochem 120:16483–16494

[332] Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B, Luo Y, Lyu D, Li Y, Shi G (2016) Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun 7:11215

[333] Zheng S, Gu T, Bao X, Sun J, Zhao J, Zhang T, Zhang L (2019) Circular RNA hsa_circ_0014243 may serve as a diagnostic biomarker for essential hypertension. Exp Ther Med 17:1728–1736

[334] Zheng S, He X, Sun J, Li Q, Zhang T, Zhang L (2020) The upregulated hsa-circRNA9102-5 may be a risk factor for essential hypertension. J Clin Lab Anal. https://doi.org/10.1002/jcla.23339

[335] Zhou T, Xie X, Li M, Shi J, Zhou JJ, Knox KS, Wang T, Chen Q, Gu W (2018a) Rat BodyMap transcriptomes reveal unique circular RNA features across tissue types and developmental stages. RNA 24:1443–1456

[336] Zhou X, Liu HY, Wang WY, Zhao H, Wang T (2018b) Hsa_circ_0102533 serves as a blood-based biomarker for non-smallcell lung cancer diagnosis and regulates apoptosis in vitro. Int J Clin Exp Pathol 11:4395–4404

[337] Zhou W, Sailani RM, Contrepois K, Zhou Y, Ahadi S, Leopold SR, Zhang MJ, Rao V, Avina M, Mishra T (2019a) Longitudinal multi-omics of host–microbe dynamics in prediabetes. Nature 569:663–671

[338] Zhou Z, Sun B, Huang S, Zhao L (2019b) Roles of circular RNAs in immune regulation and autoimmune diseases. Cell Death Dis 10:503

[339] Zhu X, Wang X, Wei S, Chen Y, Chen Y, Fan X, Han S, Wu G (2017) hsa_circ_0013958: a circular RNA and potential novel biomarker for lung adenocarcinoma. FEBS J 284:2170–2182

[340] Zhu K, Niu L, Wang J, Wang Y, Zhou J, Wang F, Cheng Y, Zhang Q, Li H (2019a) Circular RNA hsa_circ_0000885 levels are increased in tissue and serum samples from patients with osteosarcoma. Med Sci Monit 25:1499–1505

[341] Zhu X, Ding J, Wang B, Wang J, Xu M (2019b) Circular RNA DLGAP4 is down-regulated and negatively correlates with severity, inflammatory cytokine expression and pro-inflammatory gene miR-143 expression in acute ischemic stroke patients. Int J Clin Exp Pathol 12:941–948

[342] Zhuang Z-G, Zhang J-A, Luo H-L, Liu G-B, Lu Y-B, Ge N-H, Zheng B-Y, Li RX, Chen C, Wang X (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 90:264–272

[343] Zuo L, Li C, Zu J, Yao H, Yan F (2020) Circular RNA FUNDC1 improves prediction of stroke associated infection in acute ischemic stroke patients with high risk. Biosci Rep.

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