Skip to main content

Advertisement

SpringerLink
Log in

CircRNA: a novel type of biomarker for cancer

  • Review Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Circular RNAs (circRNAs) are a class of long, non-coding RNAs molecules that shape a covalently closed continuous loop which have no 5′–3′ polarity and contain no polyA tail. CircRNAs also possess relatively jarless framework and are highly tissue-specific expressed in the eukaryotic transcriptome. Emerging evidences have discovered that thousands of endogenous circRNAs are present in mammalian cells and they mediate gene expression at the transcriptional or post-transcriptional level by binding to microRNAs or other molecules and then inhibit their function. Similarly, increasing evidence indicates that circRNAs may play a role in the development of several types of diseases, including atherosclerotic vascular disease risk, neurological disorders, prion diseases, osteoarthritis and diabetes. Furthermore, circRNAs exhibit aberrant expression in multiform types of cancer, including colorectal cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma. And based on the function of circRNAs in cancer, we believe that circRNAs may serve as diagnostic or tumor promising biomarkers. Moreover, it will provide a new therapeutic target for the treatment of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cocquerelle C, Mascrez B, Hétuin D, Bailleul B. Mis-splicing yields circular RNA molecules. FASEB J. 1993;7(1):155–60.

    CAS  PubMed  Google Scholar 

  2. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7(2):e30733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9(9):e1003777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, et al. Circular intronic long noncoding RNAs. Mol Cell. 2013;51(6):792–806.

    Article  CAS  PubMed  Google Scholar 

  5. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495(7441):333–8.

    Article  CAS  PubMed  Google Scholar 

  6. Li P, Chen S, Chen H, Mo X, Li T, Shao Y, et al. Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta. 2015;444:132–6.

    Article  CAS  PubMed  Google Scholar 

  7. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–8.

    Article  CAS  PubMed  Google Scholar 

  8. Guo JU, Agarwal V, Guo H, Bartel DP. Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 2014;15(7):409.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Nair AA, Niu N, Tang X, et al. Circular RNAs and their associations with breast cancer subtypes. Oncotarget. 2016;7(49):80967–79.

    PubMed  PubMed Central  Google Scholar 

  10. Chen LL, Yang L. Regulation of circRNA biogenesis. RNA Biol. 2015;12(4):381–8.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hentze MW, Preiss T. Circular RNAs: splicing’s enigma variations. EMBO J. 2013;32(7):923–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19(2):141–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Suzuki H, Zuo Y, Wang J, Zhang MQ, Malhotra A, Mayeda A. Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing. Nucleic Acids Res. 2006;34(8):e63.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, et al. Circular RNA: a new star of noncoding RNAs. Cancer Lett. 2015;365(2):141–8.

    Article  CAS  PubMed  Google Scholar 

  15. Kulcheski FR, Christoff AP, Margis R. Circular RNAs are miRNA sponges and can be used as a new class of biomarker. J Biotechnol. 2016;238:42–51.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang HD, Jiang LH, Sun DW, Li J, Tang JH. MiR-139-5p: promising biomarker for cancer. Tumour Biol. 2015;36(3):1355–65.

    Article  CAS  PubMed  Google Scholar 

  17. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu M, Huang F, Zhang D, Ju J, Wu XB, Wang Y, et al. Heterochromatin protein HP1γ promotes colorectal cancer progression and is regulated by miR-30a. Cancer Res. 2015;75(21):4593–604.

    Article  CAS  PubMed  Google Scholar 

  19. Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z, Sharpless NE. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet. 2010;6(12):e1001233.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Li F, Zhang L, Li W, Deng J, Zheng J, An M, et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/β-catenin pathway. Oncotarget. 2015;6(8):6001–13.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ghosal S, Das S, Sen R, Basak P, Chakrabarti J. Circ2Traits: a comprehensive database for circular RNA potentially associated with disease and traits. Front Genet. 2013;4:283.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hansen TB, Kjems J, Damgaard CK. Circular RNA and miR-7 in cancer. Cancer Res. 2013;73(18):5609–12.

    Article  CAS  PubMed  Google Scholar 

  23. Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, et al. Correlation of circular RNA abundance with proliferation-exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Sci Rep. 2015;5:8057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Westholm JO, Miura P, Olson S, Shenker S, Joseph B, Sanfilippo P, et al. Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep. 2014;9(5):1966–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bahn JH, Zhang Q, Li F, Chan TM, Lin X, Kim Y, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem. 2015;61(1):221–30.

    Article  CAS  PubMed  Google Scholar 

  26. Qin M, Liu G, Huo X, Tao X, Sun X, Ge Z, et al. Hsa_circ_0001649: a circular RNA and potential novel biomarker for hepatocellular carcinoma. Cancer Biomark. 2016;16(1):161–9.

    Article  CAS  PubMed  Google Scholar 

  27. Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 2016;7:11215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25(8):981–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang XO, Wang HB, Zhang Y, Lu X, Chen LL, Yang L. Complementary sequence-mediated exon circularization. Cell. 2014;159:134–47.

    Article  CAS  PubMed  Google Scholar 

  30. Peng L, Yuan XQ, Li GC. The emerging landscape of circular RNA ciRS-7 in cancer. Oncol Rep. 2015;33(6):2669–74.

    Article  CAS  PubMed  Google Scholar 

  31. Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56(1):55–66.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou H, Arcila ML, Li Z, Lee EJ, Henzler C, Liu J, et al. Deep annotation of mouse iso-miR and iso-moR variation. Nucleic Acids Res. 2012;40(13):5864–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vicens Q, Westhof E. Biogenesis of circular RNAs. Cell. 2014;159(1):13–4.

    Article  CAS  PubMed  Google Scholar 

  34. Zhao ZJ, Shen J. Circular RNA participates in the carcinogenesis and the malignant behavior of cancer. RNA Biol. 2015;9:1–8.

    Google Scholar 

  35. Chang CW, Yu JC, Hsieh YH, Yao CC, Chao JI, Chen PM, et al. MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer. Oncotarget. 2016;7(13):16462–78.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Taulli R, Loretelli C, Pandolfi PP. From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. Nat Struct Mol Biol. 2013;20(5):541–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs. Nat Biotechnol. 2014;32(5):453–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hansen TB, Wiklund ED, Bramsen JB, Villadsen SB, Statham AL, Clark SJ, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011;30(21):4414–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen Y, Li C, Tan C, Liu X. Circular RNAs: a new frontier in the study of human diseases. J Med Genet. 2016;53(6):359–65.

    Article  PubMed  Google Scholar 

  40. Lukiw WJ, Circular RNA. circRNA) in Alzheimer’s disease (AD. Front Genet. 2013;4:307.

    PubMed  PubMed Central  Google Scholar 

  41. Capel B, Swain A, Nicolis S, Hacker A, Walter M, Koopman P, et al. Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell. 1993;73(5):1019–30.

    Article  CAS  PubMed  Google Scholar 

  42. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  43. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52.

    Article  CAS  PubMed  Google Scholar 

  44. Su H, Lin F, Deng X, Shen L, Fang Y, Fei Z, et al. Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells. J Transl Med. 2016;14(1):225.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Xia W, Qiu M, Chen R, Wang S, Leng X, Wang J, et al. Circular RNA has_circ_0067934 is upregulated in esophageal squamous cell carcinoma and promoted proliferation. Sci Rep. 2016;6:3.

    Article  Google Scholar 

  46. Zhang M, Du X. Noncoding RNAs in gastric cancer: research progress and prospects. World J Gastroenterol. 2016;22(29):6610–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dou Y, Cha DJ, Franklin JL, Higginbotham JN, Jeppesen DK, Weaver AM, et al. Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes. Sci Rep. 2016;6:37982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sasaki Y, Yamada T, Tanaka H, Peng YF, Liu WR, Shi GM, et al. Risk of recurrence in a long-term follow-up after surgery in 417 patients with hepatitis B or hepatitis C related hepatocellular carcinoma. Ann Surg. 2006;244(5):771–80.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63(5):844–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Llovet JM, Zucman-Rossi J, Pikarsky E, Gores G. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.

    Article  PubMed  Google Scholar 

  51. Shang X, Li G, Liu H, Li T, Liu J, Zhao Q, et al. Comprehensive circular RNA profiling reveals that hsa_circ_0005075, a new circular RNA biomarker, is involved in hepatocellular carcinoma development. Medicine (Baltimore). 2016;95(22):e3811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–8.

    Article  CAS  PubMed  Google Scholar 

  53. Jiang L, Liu X, Chen Z, Jin Y, Heidbreder CE, Kolokythas A, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, et al. microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res. 2008;68(10):3566–72.

    Article  CAS  PubMed  Google Scholar 

  55. Kong D, Piao YS, Yamashita S, Oshima H, Oguma K, Fushida S, et al. Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells. Oncogene. 2012;31(35):3949–60.

    Article  CAS  PubMed  Google Scholar 

  56. Li J, Zheng Y, Sun G, Xiong S. Restoration of miR-7 expression suppresses the growth of Lewis lung cancer cells by modulating epidermal growth factor receptor signaling. Oncol Rep. 2014;32(6):2511–6.

    Article  CAS  PubMed  Google Scholar 

  57. Yu L, Gong X, Sun L, Zhou Q, Lu B, Zhu L. The circular RNA Cdr1as act as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. PLoS One. 2016;11(7):e0158347.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Xu L, Zhang M, Zheng X, Yi P, Lan C, Xu M. The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2016.

  59. Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC. Cloning and characterization of three human fork head genes that comprise an FKHR-like gene subfamily. Genomics. 1998;47(2):187–99.

    Article  CAS  PubMed  Google Scholar 

  60. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7(11):847–59.

    Article  CAS  PubMed  Google Scholar 

  61. Cho EC, Kuo ML, Liu X, Yang L, Hsieh YC, Wang J, et al. Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients. Oncotarget. 2014;5(13):4834–44.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Du WW, Yang W, Fang L, Xuan J, Li H, Khorshidi A, et al. miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7. Cell Death Dis. 2014;5:e1355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. Zhang L, Dong Y, Zhu N, Tsoi H, Zhao Z, Wu CW, et al. microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer. Mol Cancer. 2014;13:124.

    Article  PubMed  PubMed Central  Google Scholar 

  65. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Tokino T, Nakamura Y. The role of p53-target genes in human cancer. Crit Rev Oncol Hematol. 2000;33(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  67. Ekoff M, Kaufmann T, Engstrom M, Motoyama N, Villunger A, Jönsson JI, et al. The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells. Blood. 2007;110:3209–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Du WW, Fang L, Yang W, Wu N, Awan FM, Yang Z, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ. 2017;24(2):357–70.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Surgery, School of Medicine, Southeast University, 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, People’s Republic of China

    He-da Zhang & Zhen-ling Ji

  2. Department of General Surgery, Institute for Minimally Invasive Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, People’s Republic of China

    He-da Zhang & Zhen-ling Ji

  3. Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China

    Lin-hong Jiang

  4. Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, People’s Republic of China

    Da-wei Sun

  5. Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China

    Jun-chen Hou

Authors
  1. He-da Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin-hong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Da-wei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun-chen Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhen-ling Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhen-ling Ji.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

This article does not contain informed consent from all individual participants.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Hd., Jiang, Lh., Sun, Dw. et al. CircRNA: a novel type of biomarker for cancer. Breast Cancer 25, 1–7 (2018). https://doi.org/10.1007/s12282-017-0793-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-017-0793-9

Keywords

Search

Navigation