Skip to main content

Advertisement

Log in

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

  • Original Article
  • Published:
Tumor Biology

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.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  7. http://www.rosettagenomics.com/.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Whiteside TL. The potential of tumor-derived exosomes for noninvasive cancer monitoring. Expert Rev Mol Diagn. 2015;1293:310.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  35. Kosaka N. Decoding the secret of cancer by means of extracellular vesicles. J Clin Med. 2016;5(2). doi:10.3390/jcm5020022.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anastasia Malek.

Ethics declarations

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Samsonov, R., Burdakov, V., Shtam, T. et al. Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer. Tumor Biol. 37, 12011–12021 (2016). https://doi.org/10.1007/s13277-016-5065-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5065-3

Keywords

Navigation