Circular RNAs Serve as Novel Biomarkers and Therapeutic Targets in Cancers

Author(s): Shuai Fang , Jinchang Pan , Chengwei Zhou , Hui Tian , Jinxian He , Weiyu Shen , Xiaofeng Jin , Xiaodan Meng , Nan Jiang , Zhaohui Gong* .

Journal Name: Current Gene Therapy

Volume 19 , Issue 2 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Circular RNAs (circRNAs) are a class of non-coding RNAs (ncRNAs) that structurally form closed loops without 5'-end cap and 3'-end poly(A) tail unlike linear RNAs. CircRNAs are widely present in eukaryotic cells with the capabilities of structural stability, high abundance and cell- /tissue-specific expression. A growing body of researches suggest that the dysregulated circRNAs are intimately relevant to the occurrence and development of cancer. In this review, we mainly discuss the differentially expressed circRNAs in cancer tissues, plasma and exosomes, which makes it possible for clinicians to use certain circRNAs as novel biomarkers for cancer diagnosis and prognosis. In particular, we primarily focus on circRNAs as potential therapeutic targets, which will provide promising applications in cancer gene therapy.

Keywords: CircRNAs, differential expression, exosomes, circulating RNAs, biomarkers, therapeutic target, cancer.

Dunham I, Kundaje A, Aldred SF, et al. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489(7414): 57-74.
Hsu MT, Coca-Prados M. Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature 1979; 280(5720): 339-40.
Arnberg AC, Van Ommen GJ, Grivell LA, Van Bruggen EF, Borst P. Some yeast mitochondrial RNAs are circular. Cell 1980; 19(2): 313-9.
Cocquerelle C, Mascrez B, Hetuin D, Bailleul B. Mis-splicing yields circular RNA molecules. FASEB J 1993; 7(1): 155-60.
Nigro JM, Cho KR, Fearon ER, et al. Scrambled exons. Cell 1991; 64(3): 607-13.
Lu T, Cui L, Zhou Y, et al. Transcriptome-wide investigation of circular RNAs in rice. RNA 2015; 21(12): 2076-87.
Broadbent KM, Broadbent JC, Ribacke U, Wirth D, Rinn JL, Sabeti PC. Strand-specific RNA sequencing in Plasmodium falciparum malaria identifies developmentally regulated long non-coding RNA and circular RNA. BMC Genomics 2015; 16: 454.
Danan M, Schwartz S, Edelheit S, Sorek R. Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res 2012; 40(7): 3131-42.
Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 2013; 19(2): 141-57.
Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013; 495(7441): 333-8.
Zhang Y, Liang W, Zhang P, et al. Circular RNAs: Emerging cancer biomarkers and targets. J Exp Clin Cancer Res 2017; 36(1): 152.
Gao Y, Wang J, Zheng Y, Zhang J, Chen S, Zhao F. Comprehensive identification of internal structure and alternative splicing events in circular RNAs. Nat Commun 2016; 7: 12060.
Gao Y, Wang J, Zhao F. CIRI: An efficient and unbiased algorithm for de novo circular RNA identification. Genome Biol 2015; 16: 4.
Zhang Y, Zhang XO, Chen T, et al. Circular intronic long noncoding RNAs. Mol Cell 2013; 51(6): 792-806.
Qu S, Yang X, Li X, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett 2015; 365(2): 141-8.
Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of CircRNAs. Cell 2015; 160(6): 1125-34.
Fang S, Guo H, Cheng Y, et al. circHECTD1 promotes the silica-induced pulmonary endothelial-mesenchymal transition via HECTD1. Cell Death Dis 2018; 9(3): 396.
Han YN, Xia SQ, Zhang YY, Zheng JH, Li W. Circular RNAs: A novel type of biomarker and genetic tools in cancer. Oncotarget 2017; 8(38): 64551-63.
Li J, Yang J, Zhou P, et al. Circular RNAs in cancer: Novel insights into origins, properties, functions and implications. Am J Cancer Res 2015; 5(2): 472-80.
Wang J, Li H. CircRNA circ_0067934 silencing inhibits the proliferation, migration and invasion of NSCLC cells and correlates with unfavorable prognosis in NSCLC. Eur Rev Med Pharmacol Sci 2018; 22(10): 3053-60.
Bahn JH, Zhang Q, Li F, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem 2015; 61(1): 221-30.
Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013; 495(7441): 384-8.
Guo JU, Agarwal V, Guo H, Bartel DP. Expanded identification and characterization of mammalian circular RNAs. Genome Biol 2014; 15(7): 409.
Hansen TB, Kjems J, Damgaard CK. Circular RNA and miR-7 in cancer. Cancer Res 2013; 73(18): 5609-12.
Reddy SD, Ohshiro K, Rayala SK, Kumar R. MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer Res 2008; 68(20): 8195-200.
Saydam O, Senol O, Wurdinger T, et al. miRNA-7 attenuation in Schwannoma tumors stimulates growth by upregulating three oncogenic signaling pathways. Cancer Res 2011; 71(3): 852-61.
Zhang X, Hu S, Zhang X, et al. MicroRNA-7 arrests cell cycle in G1 phase by directly targeting CCNE1 in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 2014; 443(3): 1078-84.
Jiang L, Liu X, Chen Z, et al. MicroRNA-7 targets IGF1R (insulin-like growth factor 1 receptor) in tongue squamous cell carcinoma cells. Biochem J 2010; 432(1): 199-205.
Sang M, Meng L, Sang Y, et al. Circular RNA ciRS-7 accelerates ESCC progression through acting as a miR-876-5p sponge to enhance MAGE-A family expression. Cancer Lett 2018; 426: 37-46.
Su C, Han Y, Zhang H, et al. CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-kappaB signalling. J Cell Mol Med 2018; 22(6): 3097-107.
Pan H, Li T, Jiang Y, et al. Overexpression of Circular RNA ciRS-7 abrogates the tumor suppressive effect of miR-7 on Gastric Cancer via PTEN/PI3K/AKT signaling pathway. J Cell Biochem 2018; 119(1): 440-6.
Chen G, Shi Y, Liu M, Sun J. circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma. Cell Death Dis 2018; 9(2): 175.
Li Y, Zheng F, Xiao X, et al. CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep 2017; 18(9): 1646-59.
Zheng Q, Bao C, Guo W, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun 2016; 7: 11215.
Yang W, Du WW, Li X, Yee AJ, Yang BB. Foxo3 activity promoted by non-coding effects of circular RNA and Foxo3 pseudogene in the inhibition of tumor growth and angiogenesis. Oncogene 2016; 35(30): 3919-31.
Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res 2016; 44(6): 2846-58.
Du WW, Yang W, Chen Y, et al. Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. Eur Heart J 2017; 38(18): 1402-12.
Yang Q, Du WW, Wu N, et al. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. Cell Death Differ 2017; 24(9): 1609-20.
Wang Y, Wang Z. Efficient backsplicing produces translatable circular mRNAs. RNA 2015; 21(2): 172-9.
Schneider T, Bindereif A. Circular RNAs: Coding or noncoding? Cell Res 2017; 27(6): 724-5.
Zhang M, Huang N, Yang X, et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene 2018; 37(13): 1805-14.
Zhang M, Xin Y. Circular RNAs: A new frontier for cancer diagnosis and therapy. J Hematol Oncol 2018; 11(1): 21.
Gridelli C, Rossi A, Carbone DP, et al. Non-small-cell lung cancer. Nat Rev Dis Primers 2015; 1: 15009.
Carninci P, Kasukawa T, Katayama S, et al. The transcriptional landscape of the mammalian genome. Science 2005; 309(5740): 1559-63.
Zong L, Sun Q, Zhang H, et al. Increased expression of circRNA_102231 in lung cancer and its clinical significance. Biomed Pharmacother 2018; 102: 639-44.
Hang D, Zhou J, Qin N, et al. A novel plasma circular RNA circFARSA is a potential biomarker for non-small cell lung cancer. Cancer Med 2018; 7(6): 2783-91.
Guarnerio J, Bezzi M, Jeong JC, et al. Oncogenic role of fusion-CircRNAs derived from cancer-associated chromosomal translocations. Cell 2016; 165(2): 289-302.
Tan S, Gou Q, Pu W, et al. Circular RNA F-circEA produced from EML4-ALK fusion gene as a novel liquid biopsy biomarker for non-small cell lung cancer. Cell Res 2018; 28(6): 693-5.
Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: A global overview and recent trends. Eur Urol 2017; 71(1): 96-108.
Yang C, Yuan W, Yang X, et al. Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression. Mol Cancer 2018; 17(1): 19.
Torre LA, Bray F, Siegel RL, et al. CA Cancer J Clin 2015; 65(2): 87-108.
Chen D, Zhang C, Lin J, Song X, Wang H. Screening differential circular RNA expression profiles reveal that hsa_circ_0128298 is a biomarker in the diagnosis and prognosis of hepatocellular carcinoma. Cancer Manag Res 2018; 10: 1275-83.
Yu J, Xu QG, Wang ZG, et al. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J Hepatol 2018; 68(6): 1214-27.
Li T, Shao Y, Fu L, et al. Plasma circular RNA profiling of patients with gastric cancer and their droplet digital RT-PCR detection. J Mol Med 2018; 96(1): 85-96.
Zhang J, Liu H, Hou L, et al. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression. Mol Cancer 2017; 16(1): 151.
Zhao Q, Chen S, Li T, Xiao B, Zhang X. Clinical values of circular RNA 0000181 in the screening of gastric cancer. J Clin Lab Anal 2018; 32(4)e22333
Huang M, He YR, Liang LC, Huang Q, Zhu ZQ. Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer. World J Gastroenterol 2017; 23(34): 6330-8.
Chen S, Li T, Zhao Q, Xiao B, Guo J. Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer. Clin Chim Acta 2017; 466: 167-71.
Zhuo F, Lin H, Chen Z, Huang Z, Hu J. The expression profile and clinical significance of circRNA0003906 in colorectal cancer. OncoTargets Ther 2017; 10: 5187-93.
Wang F, Wang J, Cao X, Xu L, Chen L. Hsa_circ_0014717 is downregulated in colorectal cancer and inhibits tumor growth by promoting p16 expression. Biomed Pharmacother 2018; 98: 775-82.
Kun-Peng Z, Xiao-Long M, Chun-Lin Z. Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1. Int J Biol Sci 2018; 14(3): 321-30.
Li W, Zhong C, Jiao J, et al. Characterization of hsa_circ_0004277 as a new biomarker for acute myeloid leukemia via circular RNA profile and bioinformatics analysis. Int J Mol Sci 2017; 18(3)E597
Xuan L, Qu L, Zhou H, et al. Circular RNA: A novel biomarker for progressive laryngeal cancer. Am J Transl Res 2016; 8(2): 932-9.
Xia W, Qiu M, Chen R, et al. Circular RNA has_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation. Sci Rep 2016; 6: 35576.
Vitiello M, Tuccoli A, Poliseno L. Long non-coding RNAs in cancer: implications for personalized therapy. Cell Oncol (Dordr) 2015; 38(1): 17-28.
Hsiao KY, Lin YC, Gupta SK, et al. Noncoding effects of circular RNA CCDC66 promotes colon cancer growth and metastasis. Cancer Res 2017; 77(9): 2339-50.
Tian H, Zhou C, Yang J, Li J, Gong Z. Long and short noncoding RNAs in lung cancer precision medicine: Opportunities and challenges. Tumour Biol 2017; 39(4)1010428317697578
Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 2015; 22(3): 256-64.
Yang J, Meng X, Pan J, et al. CRISPR/Cas9-mediated noncoding RNA editing in human cancers. RNA Biol 2018; 15(1): 35-43.
Salsman J, Masson JY, Orthwein A, Dellaire G. CRISPR/Cas9 gene editing: From basic mechanisms to improved strategies for enhanced genome engineering in vivo. Curr Gene Ther 2017; 17(4): 263-74.
Piwecka M, Glazar P, Hernandez-Miranda LR, et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 2017; 357(6357)eaam8526
Strutt SC, Torrez RM, Kaya E, Negrete OA, Doudna JA. RNA-dependent RNA targeting by CRISPR-Cas9. eLife 2018; 7e32724
Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology 2017; 66(4): 1151-64.
Li X, Wang J, Zhang C, et al. Circular RNA circITGA7 inhibits colorectal cancer growth and metastasis by modulating the Ras pathway and upregulating transcription of its host gene ITGA7. J Pathol 2018; 246(2): 166-79.
Kristensen LS, Hansen TB, Veno MT, Kjems J. Circular RNAs in cancer: Opportunities and challenges in the field. Oncogene 2018; 37(5): 555-65.
Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017; 546(7659): 498-503.
Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: A promising biomarker for cancer diagnosis. Cell Res 2015; 25(8): 981-4.
Dou Y, Cha DJ, Franklin JL, et al. Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes. Sci Rep 2016; 6: 37982.
Li Z, Yanfang W, Li J, et al. Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer. Cancer Lett 2018; 432: 237-50.
Judge AD, Robbins M, Tavakoli I, et al. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. J Clin Invest 2009; 119(3): 661-73.
Du WW, Fang L, Yang W, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ 2017; 24(2): 357-70.
Rybak-Wolf A, Stottmeister C, Glazar P, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 2015; 58(5): 870-85.
Gao Y, Zhao F. Computational strategies for exploring circular RNAs. Trends Genet 2018; 34(5): 389-400.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [125 - 133]
Pages: 9
DOI: 10.2174/1566523218666181109142756
Price: $58

Article Metrics

PDF: 24