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Tumor Biology

, Volume 37, Issue 9, pp 12011–12021 | Cite as

Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer

  • Roman Samsonov
  • Vladimir Burdakov
  • Tatiana Shtam
  • Zamira Radzhabovа
  • Dmitry Vasilyev
  • Evgenia Tsyrlina
  • Sergey Titov
  • Michail Ivanov
  • Lev Berstein
  • Michael Filatov
  • Nikolay Kolesnikov
  • Hava Gil-Henn
  • Anastasia MalekEmail author
Original Article

Abstract

Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue’s micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity.

Keywords

Thyroid cancer Exosomes MicroRNA Diagnostics 

Notes

Acknowledgments

This study was supported by Oncosystem Ltd. for (to R.S. and A.M.) and by grants from the Helmsley Trust Fund (to H.G.H).

Compliance with ethical standards

The study had Ethical Committee of N.N. Petrov Institute of Oncology approval. Informed consent was obtained from all individual participants included in the study.

Conflicts of interest

None

References

  1. 1.
    Gharib H. Changing trends in thyroid practice: understanding nodular thyroid disease. Endocr Pract. 2004;10(1):31–9. doi: 10.4158/EP.10.1.31.CrossRefPubMedGoogle Scholar
  2. 2.
    Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab. 2008;22(6):901–11. doi: 10.1016/j.beem.2008.09.019.CrossRefPubMedGoogle Scholar
  3. 3.
    Kato MA, Fahey 3rd TJ. Molecular markers in thyroid cancer diagnostics. Surg Clin North Am. 2009;89(5):1139–55. doi: 10.1016/j.suc.2009.06.012.CrossRefPubMedGoogle Scholar
  4. 4.
    Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, et al. A large multicenter correlation study of thyroid nodule cytopathology and histopathology. Thyroid. 2011;21(3):243–51. doi: 10.1089/thy.2010.0243.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yip L, Kelly L, Shuai Y, Armstrong MJ, Nikiforov YE, Carty SE, et al. MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann Surg Oncol. 2011;18(7):2035–41. doi: 10.1245/s10434-011-1733-0.CrossRefPubMedGoogle Scholar
  6. 6.
    Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol. 2014;9:287–314. doi: 10.1146/annurev-pathol-012513-104715.CrossRefPubMedGoogle Scholar
  7. 7.
  8. 8.
    Lee JC, Gundara JS, Glover A, Serpell J, Sidhu SB. MicroRNA expression profiles in the management of papillary thyroid cancer. Oncologist. 2014;19(11):1141–7. doi: 10.1634/theoncologist.2014-0135.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676–90. doi: 10.1016/j.cell.2014.09.050.CrossRefGoogle Scholar
  10. 10.
    Dettmer MS, Perren A, Moch H, Komminoth P, Nikiforov YE, Nikiforova MN. MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights. J Mol Endocrinol. 2014;52(2):181–9. doi: 10.1530/JME-13-0266.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhang Y, Zhong Q, Chen X, Fang J, Huang Z. Diagnostic value of microRNAs in discriminating malignant thyroid nodules from benign ones on fine-needle aspiration samples. Tumour Biol. 2014;35(9):9343–53. doi: 10.1007/s13277-014-2209-1.CrossRefPubMedGoogle Scholar
  12. 12.
    Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014;11(3):145–56. doi: 10.1038/nrclinonc.2014.5.CrossRefPubMedGoogle Scholar
  13. 13.
    Yu S, Liu Y, Wang J, Guo Z, Zhang Q, Yu F, et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012;97(6):2084–92. doi: 10.1210/jc.2011-3059.CrossRefPubMedGoogle Scholar
  14. 14.
    Lee JC, Zhao JT, Clifton-Bligh RJ, Gill A, Gundara JS, Ip JC, et al. MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer. 2013;119(24):4358–65. doi: 10.1002/cncr.28254.CrossRefPubMedGoogle Scholar
  15. 15.
    Cantara S, Pilli T, Sebastiani G, Cevenini G, Busonero G, Cardinale S, et al. Circulating miRNA95 and miRNA190 are sensitive markers for the differential diagnosis of thyroid nodules in a Caucasian population. J Clin Endocrinol Metab. 2014;99(11):4190–8. doi: 10.1210/jc.2014-1923.CrossRefPubMedGoogle Scholar
  16. 16.
    Lee YS, Lim YS, Lee JC, Wang SG, Park HY, Kim SY, et al. Differential expression levels of plasma-derived miR-146b and miR-155 in papillary thyroid cancer. Oral Oncol. 2015;51(1):77–83. doi: 10.1016/j.oraloncology.2014.10.006.CrossRefPubMedGoogle Scholar
  17. 17.
    Sato-Kuwabara Y, Melo SA, Soares FA, Calin GA. The fusion of two worlds: non-coding RNAs and extracellular vesicles—diagnostic and therapeutic implications (review). Int J Oncol. 2015;46(1):17–27. doi: 10.3892/ijo.2014.2712.PubMedGoogle Scholar
  18. 18.
    Chen WX, Cai YQ, Lv MM, Chen L, Zhong SL, Ma TF, et al. Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs. Tumour Biol. 2014;35(10):9649–59. doi: 10.1007/s13277-014-2242-0.CrossRefPubMedGoogle Scholar
  19. 19.
    Hannafon BN, Carpenter KJ, Berry WL, Janknecht R, Dooley WC, Ding WQ. Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA). Mol Cancer. 2015;14:133. doi: 10.1186/s12943-015-0400-7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26(5):707–21. doi: 10.1016/j.ccell.2014.09.005.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, et al. Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS One. 2014;9(4):e92921. doi: 10.1371/journal.pone.0092921.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Fujita Y, Kuwano K, Ochiya T, Takeshita F. The impact of extracellular vesicle-encapsulated circulating microRNAs in lung cancer research. BioMed Res Int. 2014;2014:486413. doi: 10.1155/2014/486413.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Que R, Ding G, Chen J, Cao L. Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma. World J Surg Oncol. 2013;11:219. doi: 10.1186/1477-7819-11-219.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zoller M. Pancreatic cancer diagnosis by free and exosomal miRNA. World J Gastrointest Pathophysiol. 2013;4(4):74–90. doi: 10.4291/wjgp.v4.i4.74.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Whiteside TL. The potential of tumor-derived exosomes for noninvasive cancer monitoring. Expert Rev Mol Diagn. 2015;1293:310.Google Scholar
  26. 26.
    Lee JC, Zhao JT, Gundara J, Serpell J, Bach LA, Sidhu S. Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. J Surg Res. 2015;196(1):39–48. doi: 10.1016/j.jss.2015.02.027.CrossRefPubMedGoogle Scholar
  27. 27.
    Mestdagh P, Van Vlierberghe P, De Weer A, Muth D, Westermann F, Speleman F, et al. A novel and universal method for microRNA RT-qPCR data normalization. Genome Biol. 2009;10(6):R64. doi: 10.1186/gb-2009-10-6-r64.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Benes V, Castoldi M. Expression profiling of microRNA using real-time quantitative PCR, how to use it and what is available. Methods. 2010;50(4):244–9. doi: 10.1016/j.ymeth.2010.01.026.CrossRefPubMedGoogle Scholar
  29. 29.
    Ferraz C, Lorenz S, Wojtas B, Bornstein SR, Paschke R, Eszlinger M. Inverse correlation of miRNA and cell cycle-associated genes suggests influence of miRNA on benign thyroid nodule tumorigenesis. J Clin Endocrinol Metab. 2013;98(1):E8–16. doi: 10.1210/jc.2012-2564.CrossRefPubMedGoogle Scholar
  30. 30.
    Suresh R, Sethi S, Ali S, Giorgadze T, Sarkar FH. Differential expression of MicroRNAs in papillary thyroid carcinoma and their role in racial disparity. J Cancer Sci Ther. 2015;7(5):145–54. doi: 10.4172/1948-5956.1000340.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Xiong Y, Kotian S, Zeiger MA, Zhang L, Kebebew E. miR-126-3p inhibits thyroid cancer cell growth and metastasis, and is associated with aggressive thyroid cancer. PLoS One. 2015;10(8):e0130496. doi: 10.1371/journal.pone.0130496.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Boufraqech M, Zhang L, Jain M, Patel D, Ellis R, Xiong Y, et al. miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr Relat Cancer. 2014;21(4):517–31. doi: 10.1530/ERC-14-0077.CrossRefPubMedGoogle Scholar
  33. 33.
    Gu Y, Li D, Luo Q, Wei C, Song H, Hua K, et al. MicroRNA-145 inhibits human papillary cancer TPC1 cell proliferation by targeting DUSP6. Int J Clin Exp Med. 2015;8(6):8590–8.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Acunzo M, Romano G, Wernicke D, Croce CM. MicroRNA and cancer—a brief overview. Adv Biol Regul. 2015;57:1–9. doi: 10.1016/j.jbior.2014.09.013.CrossRefPubMedGoogle Scholar
  35. 35.
    Kosaka N. Decoding the secret of cancer by means of extracellular vesicles. J Clin Med. 2016;5(2). doi: 10.3390/jcm5020022.
  36. 36.
    Swierniak M, Wojcicka A, Czetwertynska M, Stachlewska E, Maciag M, Wiechno W, et al. In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma. J Clin Endocrinol Metab. 2013;98(8):E1401–9. doi: 10.1210/jc.2013-1214.CrossRefPubMedGoogle Scholar
  37. 37.
    Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab. 2008;93(5):1600–8. doi: 10.1210/jc.2007-2696.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Agretti P, Ferrarini E, Rago T, Candelieri A, De Marco G, Dimida A, et al. MicroRNA expression profile helps to distinguish benign nodules from papillary thyroid carcinomas starting from cells of fine-needle aspiration. Eur J Endocrinol. 2012;167(3):393–400. doi: 10.1530/EJE-12-0400.CrossRefPubMedGoogle Scholar
  39. 39.
    Whiteside TL. The potential of tumor-derived exosomes for noninvasive cancer monitoring. Expert Rev Mol Diagn. 2015;15(10):1293–310. doi: 10.1586/14737159.2015.1071666.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lowry MC, Gallagher WM, O’Driscoll L. The role of exosomes in breast cancer. Clin Chem. 2015;61(12):1457–65. doi: 10.1373/clinchem.2015.240028.CrossRefPubMedGoogle Scholar
  41. 41.
    Taverna S, Giallombardo M, Gil-Bazo I, Carreca AP, Castiglia M, Chacartegui J, et al. Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: critical analysis of evidence and potential role in clinical practice. Oncotarget. 2016. 10.18632/oncotarget.7638.Google Scholar
  42. 42.
    Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN, Hughes SM, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci U S A. 2014;111(41):14888–93. doi: 10.1073/pnas.1408301111.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Koga K, Matsumoto K, Akiyoshi T, Kubo M, Yamanaka N, Tasaki A, et al. Purification, characterization and biological significance of tumor-derived exosomes. Anticancer Res. 2005;25(6A):3703–7.PubMedGoogle Scholar
  44. 44.
    Lozupone F, Kont V, Logozzi A, Talpsepp K, Oja T, Kubo A, et al. TM9SF4 level of expression on exosomes as new marker of malignancy in human cancer. First scientific meeting of ISEV-International Society for Extracellular Vesicles April 18-21 2012. Gothenburg: University of Gothenburg; 2012. p. 19.Google Scholar
  45. 45.
    Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177–82. doi: 10.1038/nature14581.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ferracin M, Lupini L, Salamon I, Saccenti E, Zanzi MV, Rocchi A, et al. Absolute quantification of cell-free microRNAs in cancer patients. Oncotarget. 2015;6(16):14545–55.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Madhavan B, Yue S, Galli U, Rana S, Gross W, Muller M, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer. 2015;136(11):2616–27. doi: 10.1002/ijc.29324.CrossRefPubMedGoogle Scholar
  48. 48.
    Aragon Han P, Weng CH, Khawaja HT, Nagarajan N, Schneider EB, Umbricht CB, et al. MicroRNA expression and association with clinicopathologic features in papillary thyroid cancer: a systematic review. Thyroid. 2015. doi: 10.1089/thy.2015.0193.PubMedGoogle Scholar
  49. 49.
    Dettmer M, Perren A, Moch H, Komminoth P, Nikiforov YE, Nikiforova MN. Comprehensive MicroRNA expression profiling identifies novel markers in follicular variant of papillary thyroid carcinoma. Thyroid. 2013;23(11):1383–9. doi: 10.1089/thy.2012.0632.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Roman Samsonov
    • 1
    • 2
  • Vladimir Burdakov
    • 3
    • 4
  • Tatiana Shtam
    • 3
    • 4
  • Zamira Radzhabovа
    • 2
  • Dmitry Vasilyev
    • 2
  • Evgenia Tsyrlina
    • 2
  • Sergey Titov
    • 5
  • Michail Ivanov
    • 5
  • Lev Berstein
    • 2
  • Michael Filatov
    • 3
    • 4
  • Nikolay Kolesnikov
    • 5
  • Hava Gil-Henn
    • 6
  • Anastasia Malek
    • 1
    • 2
    • 6
    Email author
  1. 1.Oncosystem LtdSaint-PetersburgRussia
  2. 2.NN Petrov Institute of OncologySaint-PetersburgRussia
  3. 3.FSBI Petersburg Nuclear Physics InstituteGatchinaRussia
  4. 4.Peter the Great St. Petersburg Polytechnic UniversitySaint-PetersburgRussia
  5. 5.Institute of Molecular and Cellular Biology SB RASNovosibirskRussia
  6. 6.Faculty of Medicine in the GalileeBar-Ilan UniversitySafedIsrael

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