Skip to main content

Advertisement

Springer Nature Link
Log in

Analysis of serum microRNA in exosomal vehicles of papillary thyroid cancer

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

In this study, we investigated the profile of microRNAs (miRNAs) contained in exosomes secreted in the serum of patients with papillary thyroid cancer (PTC).

Methods

Exosome were isolated by adding ExoQuick Exosome Precipitation Solution. Dynamic light scattering (DLS) and western blotting analysis were used to ensure the quality of exosomes. The expression levels of miRNAs were investigated using custom-designed TaqMan Advanced miRNA Array Cards in the screening cohort and using specific TaqMan Advanced MicroRNA Assays in the validation cohort.

Results

We identified miR24-3p, miR146a-5p, miR181a-5p and miR382-5p with different expression levels in two different series of 56 and 58 PTC patients as compared with healthy controls. Significant differences in the expression of three PTC exosomal miRNAs, depending on the presence of lymph node metastasis, were detected in only one PTC series. When comparing the expression levels of some PTC-specific exosomal miRNAs with those of the same miRNAs circulating free of any encapsulation, we found a significant correlation for only miR24-3p, suggesting that only select miRNAs are secreted in exosomes.

Conclusions

Our findings demonstrate that four miRNAs are differently secreted in the exosomes of PTC patients, whereas no conclusive results were found to characterize PTCs with lymph node metastasis, suggesting caution in the use of circulating exosomal miRNA expression levels as lymph node metastasis biomarkers. Further investigation into the mechanisms governing miRNA secretion in tumor cells are required.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

Data availability

The data that support the findings of this study are available on request from the corresponding author.

References

  1. M.E. Cabanillas, D.G. McFadden, C. Durante, Thyroid cancer. Lancet 388(10061), 2783–2795 (2016)

    CAS  PubMed  Google Scholar 

  2. A. Zomer, J. van Rheenen, Implications of extracellular vesicle transfer on cellular heterogeneity in cancer: what are the potential clinical ramifications? Cancer Res. 76(8), 2071–2075 (2016)

    CAS  PubMed  Google Scholar 

  3. W. Guo, Y. Gao, N. Li, F. Shao, C. Wang, P. Wang, Z. Yang, R. Li, J. He, Exosomes: new players in cancer. Oncol. Rep. 38, 665–675 (2017)

    PubMed  PubMed Central  Google Scholar 

  4. C.F. Ruivo, B. Adem, M. Silva, S.A. Melo, The biology of cancer exosomes: insights and new perspectives. Cancer Res. 77, 6480–6488 (2017)

    CAS  PubMed  Google Scholar 

  5. M.P. Bebelman, M.J. Smit, D.M. Pegtel, S.R. Baglio, Biogenesis and function of extracellular vesicles in cancer. Pharmacol. Ther. 188, 1–11 (2018)

    CAS  PubMed  Google Scholar 

  6. K. Agarwal, M. Saji, S.M. Lazaroff, A.F. Palmer, M.D. Ringel, M.E. Paulaitis, Analysis of exosome release as a cellular response to MAPK pathway inhibition. Langmuir 31(19), 5440–5448 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. M. Xing, Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer 13(3), 184–199 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. A. Prete, P. Borges de Souza, S. Censi, M. Muzza, N. Nucci, M. Sponziello, Update on fundamental mechanisms of thyroid cancer. Front. Endocrinol. 11, 102 (2020)

    Google Scholar 

  9. S. Subramaniam, V. Jeet, J.A. Clements, J.H. Gunter, J. Batra, Emergence of microRNAs as key players in cancer cell metabolism. Clin. Chem. 65(9), 1090–1101 (2019)

    CAS  PubMed  Google Scholar 

  10. K. Babaei, S. Shams, A. Keymoradzadeh, S. Vahidi, P. Hamami, R. Khaksar, S.E. Norollahi, A.A. Samadani, An insight of microRNAs performance in carcinogenesis and tumorigenesis; an overview of cancer therapy. Life Sci. 240, 117077 (2020)

    CAS  PubMed  Google Scholar 

  11. A.Z. Syeda, S.S.S. Langden, C. Munkhzul, M. Lee, S.J. Song, Regulatory mechanism of microRNA expression in cancer. Int. J. Mol. Sci. 21(5), 1723 (2020)

    CAS  Google Scholar 

  12. M. Celano, F. Rosignolo, V. Maggisano, V. Pecce, M. Iannone, D. Russo, S. Bulotta, MicroRNAs as biomarkers in thyroid carcinoma. Int. J. Genom. 2017, 6496570 (2017)

  13. M. Swierniak, A. Wojcicka, M. Czetwertynska, E. Stachlewska, M. Maciag, W. Wiechno, B. Gornicka, M. Bogdanska, L. Koperski, A. de la Chapelle, K. Jazdzewski, In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 98(8), E1401–E1409 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Y. Peng, C. Li, D.C. Luo, J.W. Ding, W. Zhang, G. Pan, Expression profile and clinical significance of microRNAs in papillary thyroid carcinoma. Molecules 19(8), 11586–11599 (2014)

    PubMed  PubMed Central  Google Scholar 

  15. F. Rosignolo, M. Sponziello, L. Giacomelli, D. Russo, V. Pecce, M. Biffoni, R. Bellantone, C.P. Lombardi, L. Lamartina, G. Grani, C. Durante, S. Filetti, A. Verrienti, Identification of thyroid-associated serum microRNA profiles and their potential use in thyroid cancer follow-up. J. Endocr. Soc. 1(1), 3–13 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. F. Rosignolo, L. Memeo, F. Monzani, C. Colarossi, V. Pecce, A. Verrienti, C. Durante, G. Grani, L. Lamartina, S. Forte, D. Martinetti, D. Giuffrida, D. Russo, F. Basolo, S. Filetti, M. Sponziello, MicroRNA-based molecular classification of papillary thyroid carcinoma. Int. J. Oncol. 50(5), 1767–1777 (2017)

    CAS  PubMed  Google Scholar 

  17. D. Dai, Y. Tan, L. Guo, A. Tang, Y. Zhao, Identification of exosomal miRNA biomarkers for diagnosis of papillary thyroid cancer by small RNA sequencing. Eur. J. Endocrinol. 182(1), 111–121 (2020)

    CAS  PubMed  Google Scholar 

  18. A. Gagliardi, S. Voci, M.C. Salvatici, M. Fresta, D. Cosco, Brij-stabilized zein nanoparticles as potential drug carriers. Colloids Surf. B. Biointerfaces 201, 111647 (2021)

    CAS  PubMed  Google Scholar 

  19. V. Pecce, M. Sponziello, G. Damante, F. Rosignolo, C. Durante, L. Lamartina, G. Grani, D. Russo, C.R. Di Gioia, S. Filetti, A. Verrienti, A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency. PLoS Genet. 14(10), e1007678 (2018)

    PubMed  PubMed Central  Google Scholar 

  20. V. Maggisano, M. Celano, S.M. Lepore, M. Sponziello, F. Rosignolo, V. Pecce, A. Verrienti, F. Baldan, C. Mio, L. Allegri, M. Maranghi, R. Falcone, G. Damante, D. Russo, S. Bulotta, Human telomerase reverse transcriptase in papillary thyroid cancer: gene expression, effects of silencing and regulation by BET inhibitors in thyroid cancer cells. Endocrine 63, 545–553 (2019)

    CAS  PubMed  Google Scholar 

  21. V. Maggisano, M. Celano, G.E. Lombardo, S.M. Lepore, M. Sponziello, F. Rosignolo, A. Verrienti, F. Baldan, E. Puxeddu, C. Durante, S. Filetti, G. Damante, D. Russo, S. Bulotta, Silencing of hTERT blocks growth and migration of anaplastic thyroid cancer cells. Mol. Cell. Endocrinol. 448, 34–40 (2017)

    CAS  PubMed  Google Scholar 

  22. The Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159(3), 676–690 (2014)

  23. R. Samsonov, V. Burdakov, T. Shtam, Z. Radzhabovа, D. Vasilyev, E. Tsyrlina, S. Titov, M. Ivanov, L. Berstein, M. Filatov, N. Kolesnikov, H. Gil-Henn, A. Malek, Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer. Tumor Biol. 37(9), 12011–12021 (2016)

    CAS  Google Scholar 

  24. J.C. Lee, J.T. Zhao, J. Gundara, J. Serpell, L.A. Bach, S. Sidhu, Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. J. Surg. Res. 196(1), 39–48 (2015)

    CAS  PubMed  Google Scholar 

  25. K. Jiang, G. Li, W. Chen, L. Song, T. Wei, Z. Li, R. Gong, J. Lei, H. Shi, J. Zhu, Plasma exosomal miR-146b-5p and miR-222-3p are potential biomarkers for lymph node metastasis in papillary thyroid carcinomas. OncoTargets Ther. 13, 1311–1319 (2020)

    CAS  Google Scholar 

  26. Q. Pan, Z.J. Jiangman, M. Li, X. Liu, Y. Xu, W. Li, S. Wu, Z. Su, Exosomal miRNAs are potential diagnostic biomarkers between malignant and benign thyroid nodules based on next-generation sequencing. Carcinogenesis 41(1), 18–24 (2020)

    CAS  PubMed  Google Scholar 

  27. F. Wu, F. Li, X. Lin, F. Xu, R.R. Cui, J.Y. Zhong, T. Zhu, S.K. Shan, X.B. Liao, L.Q. Yuan, Z.H. Mo, Exosomes increased angiogenesis in papillary thyroid cancer microenvironment. Endocr. Relat. Cancer 26(5), 525–538 (2019)

    CAS  PubMed  Google Scholar 

  28. Y.W. Yi, J.H. Lee, S. Kim, C. Pack, D.H. Ha, S.R. Park, J. Youn, B.S. Cho, Advances in analysis of biodistribution of exosomes by molecular imaging. Int. J. Mol. Sci. 21(2), 665 (2020)

    CAS  PubMed Central  Google Scholar 

  29. S. Bulotta, M. Celano, G. Costante, D. Russo, Novel therapeutic options for radioiodine-refractory thyroid cancer: redifferentiation and beyond. Curr. Opin. Oncol. 32(1), 13–19 (2020)

    CAS  PubMed  Google Scholar 

  30. L. Lamartina, G. Grani, M. Biffoni, L. Giacomelli, G. Costante, S. Lupo, M. Maranghi, K. Plasmati, M. Sponziello, F. Trulli, A. Verrienti, S. Filetti, C. Durante, Risk stratification of neck lesions detected sonographically during the follow-up of differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 101(8), 3036–3044 (2016)

    CAS  PubMed  Google Scholar 

  31. G. Pogliaghi, Liquid biopsy in thyroid cancer: from circulating biomarkers to a new prospective of tumor monitoring and therapy. Minerva Endocrinol. 46(1), 45–61 (2021). https://doi.org/10.23736/S2724-6507.20.03339-8

    Article  Google Scholar 

  32. Y. Zhang, D. Xu, J. Pan, Z. Yang, M. Chen, J. Han, S. Zhang, L. Sun, H. Qiao, Dynamic monitoring of circulating microRNAs as a predictive biomarker for the diagnosis and recurrence of papillary thyroid carcinoma. Oncol. Lett. 13(6), 4252–4266 (2017)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. J.C. Lee, J.T. Zhao, R.J. Clifton-Bligh, A. Gill, J.S. Gundara, C. Ip, J. Glover, A. Sywak, M.S. Delbridge, L.W. Robinson, B.G. Sidhu, S.B.: MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer 119(24), 4358–4365 (2013)

    CAS  PubMed  Google Scholar 

  34. R. Benedetti, C. Papulino, G. Sgueglia, U. Chianese, T. De Marchi, F. Iovino, D. Rotili, A. Mai, E. Niméus, C. Dell’Aversana, L. Altucci, Regulatory interplay between miR-181a-5p and estrogen receptor signaling cascade in breast cancer. Cancers 13(3), 543 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. T. Bjørnetrø, K.R. Redalen, S. Meltzer, N.S. Thusyanthan, R. Samiappan, C. Jegerschöld, K.R. Handeland, A.H. Ree, An experimental strategy unveiling exosomal microRNAs 486-5p, 181a-5p and 30d-5p from hypoxic tumour cells as circulating indicators of high-risk rectal Cancer. J. Extracell. Vesicles. 8(1), 1567219 (2019)

    PubMed  PubMed Central  Google Scholar 

  36. J.R. Jacona, C.S. Lutz, miR-146a-5p: expression, regulation, and functions in cancer. Wiley Interdiscip. Rev. RNA 10(4), e1533 (2019)

    Google Scholar 

  37. C. Yin, Q. Han, D. Xu, B. Zheng, X. Zhao, J. Zhang, SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology 8(7), 1601479 (2019)

    PubMed  PubMed Central  Google Scholar 

  38. D.-L. Yuwen, B.-B. Sheng, J. Liu, W. Wenyu, Y.-Q. Shu, MiR-146a-5p level in serum exosomes predicts therapeutic effect of cisplatin in non-small cell lung cancer. Eur. Rev. Med. Pharmacol. Sci. 21(11), 2650–2658 (2017)

    PubMed  Google Scholar 

  39. Y. Zhang, J. Zhao, M. Ding, Y. Su, D. Cui, C. Jiang, S. Zhao, G. Jia, X. Wang, Y. Ruan, Y. Jing, S. Xia, B. Han, Loss of exosomal miR-146a-5p from cancerassociated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis. J. Exp. Clin. Cancer Res. 39(1), 282 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Q. Wu, L. Yu, X. Lin, Q. Zheng, S. Zhang, D. Chen, X. Pan, Y. Huang, Combination of serum miRNAs with serum exosomal miRNAs in early diagnosis for non-small-cell lung cancer. Cancer Manag. Res. 12, 485–495 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. J. Wang, C. Chen, X. Yan, P. Wang, The role of miR-382-5p in glioma cell proliferation, migration and invasion. Onco Targets Ther. 12, 4993–5002 (2019)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. I.H. Lee, G. Kim, S.G. Kwak, D.W. Baek, B.W. Kang, H.J. Kim, S.Y. Park, J.S. Park, G.S. Choi, K. Hur, J.G. Kim, Predictive value of circulating miRNAs in lymph node metastasis for colon cancer. Genes. 12(2), 176 (2021)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. H. Wang, C. Chen, K. Ding, W. Zhang, J. Hou, MiR-24-3p as a prognostic indicator for multiple cancers: from a meta-analysis view. Biosci. Rep. 40(12), BSR20202938 (2020)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. M. Liang, F. Zhan, J. Zhao, Q. Li, J. Wuyang, G. Mu, D. Li, Y. Zhang, X. Huang, A panel of plasma exosomal miRNAs as potential biomarkers for differential diagnosis of thyroid nodules. Front. Genet. 11, 449 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. B.R. Haugen, E.K. Alexander, K.C. Bible, G. Doherty, S.J. Mandel, Y.E. Nikiforov, F. Pacini, G. Randolph, A. Sawka, M. Schlumberger, K.G. Schuff, S.I. Sherman, J.A. Sosa, D. Steward, R.M. Tuttle, L. Wartofsky, 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 26, 1–133 (2016)

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The manuscript was edited by Melissa Kerr.

Funding

This research was funded by PRIN2017EKMFTN_003.

Author information

Author notes

  1. These authors contributed equally: Francesca Capriglione, Antonella Verrienti

Authors and Affiliations

  1. Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100, Catanzaro, Italy

    Francesca Capriglione, Marilena Celano, Valentina Maggisano, Agnese Gagliardi, Stefania Bulotta & Diego Russo

  2. Department of translational and precision medicine, “Sapienza” University of Rome, 00161, Rome, Italy

    Antonella Verrienti, Marialuisa Sponziello, Valeria Pecce, Valerio Aceti & Cosimo Durante

  3. Department of Surgical Sciences, “Sapienza” University of Rome, 00161, Rome, Italy

    Laura Giacomelli

Authors
  1. Francesca Capriglione
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Antonella Verrienti
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Marilena Celano
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Valentina Maggisano
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Marialuisa Sponziello
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Valeria Pecce
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Agnese Gagliardi
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Laura Giacomelli
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Valerio Aceti
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Cosimo Durante
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Stefania Bulotta
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Diego Russo
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Conceptualization, F.C., A.V. and D.R.; validation, V.P. and M.S.; meth-odology, L.G. and V.A.; formal analysis, V.M., and A.G.; investigation, F.C., V.M., A.V. and M.C.; writing—original draft preparation, S.B., F.C. and A.V.; writing—review and editing, D.R., S.B.; supervision, D.R., C.D. and S.B. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Diego Russo.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

This study was conducted according to guidelines of the Declaration of Helsinki and approved by the ethics committee of Sapienza University of Rome (protocol code 1184/17 and date of approval 21/12/2017).

Consent for publication

Informed consent was obtained from all subjects involved in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Capriglione, F., Verrienti, A., Celano, M. et al. Analysis of serum microRNA in exosomal vehicles of papillary thyroid cancer. Endocrine 75, 185–193 (2022). https://doi.org/10.1007/s12020-021-02847-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02847-2

Keywords