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

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Abstract

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.

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References

  1. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  PubMed  Google Scholar 

  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):17442–17452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):654–659

    Article  CAS  PubMed  Google Scholar 

  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):5003–5008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):423–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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–D247

    Article  PubMed  Google Scholar 

  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):683–691

    Article  CAS  PubMed  Google Scholar 

  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):61–68

    Article  PubMed  Google Scholar 

  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 15:149

    Article  PubMed  PubMed Central  Google Scholar 

  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):334–345

    Article  CAS  PubMed  Google Scholar 

  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):1133–1142

    Article  PubMed  PubMed Central  Google Scholar 

  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):849–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wen Y, Han J, Chen J et al (2015) Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer 137(7):1679–1690

    Article  CAS  PubMed  Google Scholar 

  14. Wang J, Huang SK, Zhao M et al (2014) Identification of a circulating microRNA signature for colorectal cancer detection. PLoS One 9(4):e87451

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tomimaru Y, Eguchi H, Nagano H et al (2012) Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol 56(1):167–175

    Article  CAS  PubMed  Google Scholar 

  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):e109347

    Article  PubMed  PubMed Central  Google Scholar 

  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 11:374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):136–142

    Article  CAS  PubMed  Google Scholar 

  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):e5642

    Article  CAS  Google Scholar 

  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 75:153–158

    Article  CAS  PubMed  Google Scholar 

  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):1985–1992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):e47003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):298–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1619–1625

    Article  CAS  PubMed  Google Scholar 

  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):1620–1628

    Article  CAS  PubMed  Google Scholar 

  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):4781–4788

    Article  CAS  PubMed  Google Scholar 

  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):74–79

    Article  PubMed  PubMed Central  Google Scholar 

  28. Schultz NA, Dehlendorff C, Jensen BV et al (2014) MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 311(4):392–404

    Article  CAS  PubMed  Google Scholar 

  29. Chan M, Liaw CS, Ji SM et al (2013) Identification of circulating microRNA signatures for breast cancer detection. Clin Cancer Res 19(16):4477–4487

    Article  CAS  PubMed  Google Scholar 

  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):1871–1879

    Article  CAS  PubMed  Google Scholar 

  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):e107986

    Article  PubMed  PubMed Central  Google Scholar 

  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):10663–10675

    PubMed  PubMed Central  Google Scholar 

  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):118–126

    Article  CAS  PubMed  Google Scholar 

  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):275–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1633–1645

    Article  CAS  PubMed  Google Scholar 

  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.e683

    Article  Google Scholar 

  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):1751–1759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):784–791

    Article  CAS  PubMed  Google Scholar 

  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):2291–2299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):671–680

    Article  PubMed  PubMed Central  Google Scholar 

  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):2312–2324

    Article  CAS  PubMed  Google Scholar 

  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):985–993

    Article  CAS  PubMed  Google Scholar 

  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):1614–1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):4801–4809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):16923–16935

    PubMed  PubMed Central  Google Scholar 

  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):733–745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 5:11251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):5972–5982

    Article  CAS  PubMed  Google Scholar 

  49. Nadal E, Truini A, Nakata A et al (2015) A novel serum 4-microRNA signature for lung cancer detection. Sci Rep 5:12464

    Article  PubMed  PubMed Central  Google Scholar 

  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. 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):346–352

    Article  CAS  PubMed  Google Scholar 

  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):5305–5313

    Article  CAS  PubMed  Google Scholar 

  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):804–815

    Article  CAS  PubMed  Google Scholar 

  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 5:12921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 170:1–7

    Article  CAS  PubMed  Google Scholar 

  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):e0135168

    Article  PubMed  PubMed Central  Google Scholar 

  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):1241–1246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1375–1381

    Article  CAS  PubMed  Google Scholar 

  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):23382–23389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):7053–7064

    Article  PubMed  PubMed Central  Google Scholar 

  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):326–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):e0118220

    Article  PubMed  PubMed Central  Google Scholar 

  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):699–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):85551–85563

    PubMed  PubMed Central  Google Scholar 

  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:e1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 151:235–242

    Article  CAS  PubMed  Google Scholar 

  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 2:20920

    Article  Google Scholar 

  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 4:26659

    Article  PubMed  Google Scholar 

  69. Yoshioka Y, Kosaka N, Konishi Y et al (2014) Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat Commun 5:3591

    Article  PubMed  PubMed Central  Google Scholar 

  70. Yoshioka Y, Konishi Y, Kosaka N et al (2013) Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles 2:20424

    Article  Google Scholar 

  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):1757–1766

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

This study was supported by the ‘Development of Diagnostic Technology for Detection of miRNA in Body Fluids’ Grant from the Japan Agency for Medical Research and Development and New Energy and Industrial Technology Development Organization to TO.

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  1. Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Juntaro Matsuzaki & Takahiro Ochiya

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  1. Juntaro Matsuzaki
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  2. Takahiro Ochiya
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Correspondence to Takahiro Ochiya.

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Conflict of interest

TO received research grant from Kewpie Corporation, Rohto Pharmaceutical Co., Ltd., Japan Atherosclerosis Research Foundation, and Inter Stem. JM has no conflict of interest.

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Matsuzaki, J., Ochiya, T. Circulating microRNAs and extracellular vesicles as potential cancer biomarkers: a systematic review. Int J Clin Oncol 22, 413–420 (2017). https://doi.org/10.1007/s10147-017-1104-3

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  • DOI: https://doi.org/10.1007/s10147-017-1104-3

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