International Journal of Clinical Oncology

, Volume 22, Issue 3, pp 413–420

Circulating microRNAs and extracellular vesicles as potential cancer biomarkers: a systematic review

Invited Review Article


Circulating non-coding RNAs, including microRNAs and long non-coding RNAs, and the protein components of extracellular vesicles are promising biomarkers for the non-invasive detection of cancer at an early stage. This systematic review discusses the increasing number of well-designed cancer biomarker-related studies that have been published worldwide. In many of these studies, high diagnostic accuracy, which is represented as the area under the receiver operating characteristic curve being >0.8, could be achieved using combinations of circulating microRNAs. In addition, similar diagnostic accuracies were reported using long non-coding RNAs or proteins present in extracellular vesicles, although these evidences were based on a limited number of studies.


MicroRNA Long non-coding RNA Extracellular vesicle Cancer Liquid biopsy 


  1. 1.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297CrossRefPubMedGoogle Scholar
  2. 2.
    Kosaka N, Iguchi H, Yoshioka Y et al (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285(23):17442–17452CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Valadi H, Ekstrom K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659CrossRefPubMedGoogle Scholar
  4. 4.
    Arroyo JD, Chevillet JR, Kroh EM et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA 108(12):5003–5008CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Vickers KC, Palmisano BT, Shoucri BM et al (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13(4):423–433CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chou CH, Chang NW, Shrestha S et al (2016) miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res 44(D1):D239–D247CrossRefPubMedGoogle Scholar
  7. 7.
    Liu J, Gao J, Du Y et al (2012) Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer. Int J Cancer 131(3):683–691CrossRefPubMedGoogle Scholar
  8. 8.
    Muller V, Gade S, Steinbach B et al (2014) Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. Breast Cancer Res Treat 147(1):61–68CrossRefPubMedGoogle Scholar
  9. 9.
    Geng Q, Fan T, Zhang B et al (2014) Five microRNAs in plasma as novel biomarkers for screening of early-stage non-small cell lung cancer. Respir Res 15:149CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wang P, Zhuang L, Zhang J et al (2013) The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol 7(3):334–345CrossRefPubMedGoogle Scholar
  11. 11.
    Liu X, Luo HN, Tian WD et al (2013) Diagnostic and prognostic value of plasma microRNA deregulation in nasopharyngeal carcinoma. Cancer Biol Ther 14(12):1133–1142CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Toiyama Y, Takahashi M, Hur K et al (2013) Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst 105(12):849–859CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wen Y, Han J, Chen J et al (2015) Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer 137(7):1679–1690CrossRefPubMedGoogle Scholar
  14. 14.
    Wang J, Huang SK, Zhao M et al (2014) Identification of a circulating microRNA signature for colorectal cancer detection. PLoS One 9(4):e87451CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Tomimaru Y, Eguchi H, Nagano H et al (2012) Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol 56(1):167–175CrossRefPubMedGoogle Scholar
  16. 16.
    Liu M, Liu J, Wang L et al (2014) Association of serum microRNA expression in hepatocellular carcinomas treated with transarterial chemoembolization and patient survival. PLoS One 9(10):e109347CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Shen J, Liu Z, Todd NW et al (2011) Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer 11:374CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Xu J, Wu C, Che X et al (2011) Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog 50(2):136–142CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang Y, Li T, Qiu Y et al (2017) Serum microRNA panel for early diagnosis of the onset of hepatocellular carcinoma. Medicine (Baltimore) 96(2):e5642CrossRefGoogle Scholar
  20. 20.
    Yang Z, Zhang Y, Zhang X et al (2015) Serum microRNA-221 functions as a potential diagnostic and prognostic marker for patients with osteosarcoma. Biomed Pharmacother 75:153–158CrossRefPubMedGoogle Scholar
  21. 21.
    Zheng G, Du L, Yang X et al (2014) Serum microRNA panel as biomarkers for early diagnosis of colorectal adenocarcinoma. Br J Cancer 111(10):1985–1992CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sun Y, Wang M, Lin G et al (2012) Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS One 7(10):e47003CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang JL, Wang X, Yang D et al (2016) The expression of microRNA-155 in plasma and tissue is matched in human laryngeal squamous cell carcinoma. Yonsei Med J 57(2):298–305CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lv ZC, Fan YS, Chen HB et al (2015) Investigation of microRNA-155 as a serum diagnostic and prognostic biomarker for colorectal cancer. Tumour Biol 36(3):1619–1625CrossRefPubMedGoogle Scholar
  25. 25.
    Chen X, Hu Z, Wang W et al (2012) Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis. Int J Cancer 130(7):1620–1628CrossRefPubMedGoogle Scholar
  26. 26.
    Zhou J, Yu L, Gao X et al (2011) Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol 29(36):4781–4788CrossRefPubMedGoogle Scholar
  27. 27.
    Dong J, Liu Y, Liao W et al (2016) miRNA-223 is a potential diagnostic and prognostic marker for osteosarcoma. J Bone Oncol 5(2):74–79CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Schultz NA, Dehlendorff C, Jensen BV et al (2014) MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 311(4):392–404CrossRefPubMedGoogle Scholar
  29. 29.
    Chan M, Liaw CS, Ji SM et al (2013) Identification of circulating microRNA signatures for breast cancer detection. Clin Cancer Res 19(16):4477–4487CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang C, Wang C, Chen X et al (2010) Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma. Clin Chem 56(12):1871–1879CrossRefPubMedGoogle Scholar
  31. 31.
    Tan Y, Ge G, Pan T et al (2014) A serum microRNA panel as potential biomarkers for hepatocellular carcinoma related with hepatitis B virus. PLoS One 9(9):e107986CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chang PY, Chen CC, Chang YS et al (2016) MicroRNA-223 and microRNA-92a in stool and plasma samples act as complementary biomarkers to increase colorectal cancer detection. Oncotarget 7(9):10663–10675PubMedPubMedCentralGoogle Scholar
  33. 33.
    Huang Z, Huang D, Ni S et al (2010) Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer 127(1):118–126CrossRefPubMedGoogle Scholar
  34. 34.
    Matsumura T, Sugimachi K, Iinuma H et al (2015) Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer 113(2):275–281CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Torres A, Torres K, Pesci A et al (2013) Diagnostic and prognostic significance of miRNA signatures in tissues and plasma of endometrioid endometrial carcinoma patients. Int J Cancer 132(7):1633–1645CrossRefPubMedGoogle Scholar
  36. 36.
    Giraldez MD, Lozano JJ, Ramirez G et al (2013) Circulating microRNAs as biomarkers of colorectal cancer: results from a genome-wide profiling and validation study. Clin Gastroenterol Hepatol 11(6):681–688.e683CrossRefGoogle Scholar
  37. 37.
    Shin VY, Siu JM, Cheuk I et al (2015) Circulating cell-free miRNAs as biomarker for triple-negative breast cancer. Br J Cancer 112(11):1751–1759CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Liu R, Zhang C, Hu Z et al (2011) A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer 47(5):784–791CrossRefPubMedGoogle Scholar
  39. 39.
    Zhu C, Ren C, Han J et al (2014) A five-microRNA panel in plasma was identified as potential biomarker for early detection of gastric cancer. Br J Cancer 110(9):2291–2299CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Stark MS, Klein K, Weide B et al (2015) The prognostic and predictive value of melanoma-related microRNAs using tissue and serum: a microRNA expression analysis. EBioMedicine 2(7):671–680CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Johansen JS, Calatayud D, Albieri V et al (2016) The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer. Int J Cancer 139(10):2312–2324CrossRefPubMedGoogle Scholar
  42. 42.
    Guo S, Guo W, Li S et al (2016) Serum miR-16: a potential biomarker for predicting melanoma prognosis. J Invest Dermatol 136(5):985–993CrossRefPubMedGoogle Scholar
  43. 43.
    Komatsu S, Ichikawa D, Hirajima S et al (2014) Plasma microRNA profiles: identification of miR-25 as a novel diagnostic and monitoring biomarker in oesophageal squamous cell carcinoma. Br J Cancer 111(8):1614–1624CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wang Y, Gu J, Roth JA et al (2013) Pathway-based serum microRNA profiling and survival in patients with advanced stage non-small cell lung cancer. Cancer Res 73(15):4801–4809CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Meng X, Muller V, Milde-Langosch K et al (2016) Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget 7(13):16923–16935PubMedPubMedCentralGoogle Scholar
  46. 46.
    Zhang J, Song Y, Zhang C et al (2015) Circulating miR-16-5p and miR-19b-3p as two novel potential biomarkers to indicate progression of gastric cancer. Theranostics 5(7):733–745CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhou X, Zhu W, Li H et al (2015) Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis. Sci Rep 5:11251CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Madhavan D, Zucknick M, Wallwiener M et al (2012) Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer. Clin Cancer Res 18(21):5972–5982CrossRefPubMedGoogle Scholar
  49. 49.
    Nadal E, Truini A, Nakata A et al (2015) A novel serum 4-microRNA signature for lung cancer detection. Sci Rep 5:12464CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang C, Hann HW, Ye Z et al. (2016) Prospective evidence of a circulating microRNA signature as a non-invasive marker of hepatocellular carcinoma in HBV patients. Oncotarget. doi:10.18632/oncotarget.9429 Google Scholar
  51. 51.
    Zhang J, Zhang K, Bi M et al (2014) Circulating microRNA expressions in colorectal cancer as predictors of response to chemotherapy. Anticancer Drugs 25(3):346–352CrossRefPubMedGoogle Scholar
  52. 52.
    Liang H, Jiang Z, Xie G et al (2015) Serum microRNA-145 as a novel biomarker in human ovarian cancer. Tumour Biol 36(7):5305–5313CrossRefPubMedGoogle Scholar
  53. 53.
    Lin XJ, Chong Y, Guo ZW et al (2015) A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol 16(7):804–815CrossRefPubMedGoogle Scholar
  54. 54.
    Li J, Liu Y, Wang C et al (2015) Serum miRNA expression profile as a prognostic biomarker of stage II/III colorectal adenocarcinoma. Sci Rep 5:12921CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Shi SB, Wang M, Tian J et al (2016) MicroRNA 25, microRNA 145, and microRNA 210 as biomarkers for predicting the efficacy of maintenance treatment with pemetrexed in lung adenocarcinoma patients who are negative for epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations. Transl Res 170:1–7CrossRefPubMedGoogle Scholar
  56. 56.
    Yang Y, Qu A, Liu J et al (2015) Serum miR-210 contributes to tumor detection, stage prediction and dynamic surveillance in patients with bladder cancer. PLoS One 10(8):e0135168CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Lai NS, Wu DG, Fang XG et al (2015) Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma. Br J Cancer 112(7):1241–1246CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Ng EK, Chong WW, Jin H et al (2009) Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58(10):1375–1381CrossRefPubMedGoogle Scholar
  59. 59.
    Fedorko M, Stanik M, Iliev R et al (2015) Combination of miR-378 and miR-210 serum levels enables sensitive detection of renal cell carcinoma. Int J Mol Sci 16(10):23382–23389CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ono S, Oyama T, Lam S et al (2015) A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients. Oncotarget 6(9):7053–7064CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Shimomura A, Shiino S, Kawauchi J et al (2016) Novel combination of serum microRNA for detecting breast cancer in the early stage. Cancer Sci 107(3):326–334CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kojima M, Sudo H, Kawauchi J et al (2015) MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers. PLoS One 10(2):e0118220CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Geisler S, Coller J (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14(11):699–712CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Liu T, Zhang X, Gao S et al (2016) Exosomal long noncoding RNA CRNDE-h as a novel serum-based biomarker for diagnosis and prognosis of colorectal cancer. Oncotarget 7(51):85551–85563PubMedPubMedCentralGoogle Scholar
  65. 65.
    Tang J, Zhuo H, Zhang X et al (2014) A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma. Cell Death Dis 5:e1549CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Peng H, Wang J, Li J et al (2016) A circulating non-coding RNA panel as an early detection predictor of non-small cell lung cancer. Life Sci 151:235–242CrossRefPubMedGoogle Scholar
  67. 67.
    Jorgensen M, Baek R, Pedersen S et al (2013) Extracellular vesicle (EV) array: microarray capturing of exosomes and other extracellular vesicles for multiplexed phenotyping. J Extracell Vesicles 2:20920CrossRefGoogle Scholar
  68. 68.
    Jakobsen KR, Paulsen BS, Baek R et al (2015) Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. J Extracell Vesicles 4:26659CrossRefPubMedGoogle Scholar
  69. 69.
    Yoshioka Y, Kosaka N, Konishi Y et al (2014) Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat Commun 5:3591CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Yoshioka Y, Konishi Y, Kosaka N et al (2013) Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles 2:20424CrossRefGoogle Scholar
  71. 71.
    Moon PG, Lee JE, Cho YE et al (2016) Identification of developmental endothelial locus-1 on circulating extracellular vesicles as a novel biomarker for early breast cancer detection. Clin Cancer Res 22(7):1757–1766CrossRefPubMedGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2017

Authors and Affiliations

  1. 1.Division of Molecular and Cellular MedicineNational Cancer Center Research InstituteTokyoJapan

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