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A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker

Journal of Neuro-Oncology volume 136, pages 51–62 (2018)Cite this article

Abstract

Malignant gliomas, the most frequent primary brain tumors, are characterized by a dismal prognosis. Reliable biomarkers complementary to neuroradiology in the differential diagnosis of gliomas and monitoring for post-surgical progression are unmet needs. Altered expression of several microRNAs in tumour tissues from patients with gliomas compared to normal brain tissue have been described, thus supporting the rationale of using microRNA-based biomarkers. Although different circulating microRNAs were proposed in association with gliomas, they have not been introduced into clinical practice so far. Blood samples were collected from patients with high and low grade gliomas, both before and after surgical resection, and the expression of miR-21, miR-222 and miR-124-3p was measured in exosomes isolated from serum. The expression levels of miR-21, miR-222 and miR-124-3p in serum exosomes of patients with high grade gliomas were significantly higher than those of low grade gliomas and healthy controls and were sharply decreased in samples obtained after surgery. The analysis of miR-21, miR-222 and miR-124-3p in serum exosomes of patients affected by gliomas can provide a minimally invasive and innovative tool to help the differential diagnosis of gliomas at their onset in the brain and predict glioma grading and non glial metastases before surgery.

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References

  1. Schwartzbaum JA, Fisher JL, Aldape KD et al (2006) Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2:494–503

    Article  PubMed  Google Scholar 

  2. Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820

    Article  PubMed  Google Scholar 

  3. Stupp R (2006) Temozolomide: a milestone in neuro-oncology and beyond? Expert Rev Anticancer Ther 6(8):1187–1204

    Article  PubMed  Google Scholar 

  4. Brandsma D, Stalpers L, Taal W et al, 2008. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9(5):453–461

    Article  PubMed  Google Scholar 

  5. Westphal M, Lamszus K (2015) Circulating biomarkers for gliomas. Nat Rev Neurol 11(10):556–566

    Article  CAS  PubMed  Google Scholar 

  6. Kosaka N, Yoshioka Y, Fujita Y et al (2016) Versatile roles of extracellular vesicles in cancer. J Clin Invest 126(49):1163–1172

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kalluri R (2016) The biology and function of exosomes in cancer. J Clin Invest 126(4):1208–1215

    Article  PubMed  PubMed Central  Google Scholar 

  8. Skog J, Würdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jonas S, Izaurralde E (2015) Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 7:421–433

    Article  Google Scholar 

  10. Touat M, Duran-Peña A, Alentorn A et al (2015) Emerging circulating biomarkers in glioblastoma: promises and challenges. Expert Rev Mol Diagn 15(10):1311–1323

    Article  CAS  PubMed  Google Scholar 

  11. Siegal T, Charbit H, Paldor I et al (2016) Dynamics of circulating hypoxia-mediated miRNAs and tumor response in patients with high-grade glioma treated with bevacizumab. J Neurosur 125(4):1008–1015

    Article  Google Scholar 

  12. Li C, Sun J, Xiang Q et al (2016) Prognostic role of microRNA-21 expression in gliomas: a meta-analysis. J Neuroncol 130:11–17

    Article  CAS  Google Scholar 

  13. Zhang R, Pang B, Xin T et al (2016) Plasma miR-221/222 family as novel descriptive and prognostic biomarkers for glioma. Mol Neurobiol 53:1452–1460

    Article  CAS  PubMed  Google Scholar 

  14. Khalil S, Fabbri E, Santangelo A et al (2016) miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma. Oncotarget 7(19):28195–28206

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hayes J, Thygesen H, Gregory W et al (2016) A validated microRNA profile with predictive potential in glioblastoma patients treated with bevacizumab. Mol Oncol 10(8):1296–1304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Thery C, Amigorena S, Raposo G et al (2016) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. doi:10.1002/0471143030.cb0322s30

    Google Scholar 

  17. Laurent LC, Alexander RP (2015) Exosome isolation from serum using Exoquick reagent Protocol Exchange, Extracellular RNA Communication Consortium

  18. Edh M, Lotvall J, Malmhall C et al (2012) Importance of RNA isolation methods for analysis of exosomal RNA: evaluation of different methods. Molecular Immunol 50(4):278–286

    Article  Google Scholar 

  19. Moldoval L, Battle K, Wang Y et al (2013) Analyzing the circulating miRNAs in exosomes/extracellular vescicles from serum or plasma by qRT-PCR. Methods Mol Biol 1024:129–145

    Article  Google Scholar 

  20. Marka I, Terejanszky P, Gyurcsanyi RE (2015) A method based on light scattering to estimate the concentration of virus particles without the need for virus particle standards. MethodsX 2:91–99

    Article  Google Scholar 

  21. Jia S, Zocco D, Samuels ML et al (2014) Emerging technologies in extracellular vesicle-based molecular diagnostics. Expert Rev Mol Diagn (3):307–321

  22. Kumar D, Gupta D, Shankar S et al (2015) Biomolecular characterization of exosomes released from cancer stem cells: possible implications for biomarker and treatment of cancer. Oncotarget 6(5):3280–3291

    Article  PubMed  Google Scholar 

  23. Melo SA, Luecke LB, Kahlert C et al (2015) Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523:178–184

    Article  Google Scholar 

  24. Wang Q, Li P, Li A et al (2012) Plasma specific miRNAs as predictive biomarkers for diagnosis and prognosis of glioma. J Exp Clin Cancer Res 31:97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Berthois Y, Delfino C, Metellus P et al (2014) Differential expression of miR200a-3p and miR21 in grade II-III and grade IV gliomas: evidence that miR200a-3p is regulated by O6-methylguanine methyltransferase and promotes temozolomide responsiveness. Cancer Biol Ther 15(7):938–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Qu S, Guan J, Liu Y (2015) Identification of microRNAs as novel biomarkers for glioma detection: a meta-analysis based on 11 articles. J Neurol Sci 348:181–187

    Article  CAS  PubMed  Google Scholar 

  27. Mc Lendon R, Friedman A, Bigner D et al (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  CAS  Google Scholar 

  28. Roth P, Wischhusen J, Happold C et al (2011) A specific miRNA signature in the peripheral bllod of glioblastoma patients. J Neurochem 118(3):449–457

    Article  CAS  PubMed  Google Scholar 

  29. Ilhan-Mutlu A, Wagner L, Wohrer A et al (2012) Plasma MicroRNA-21 concentration may be a useful biomarker in glioblastoma patients. Cancer Invest 30(8):615–621

    Article  CAS  PubMed  Google Scholar 

  30. Manterola L, Guruceaga E, Gallego Perez-Larraya J et al (2014) A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 16(4):520–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dong L, Li Y, Han C et al (2014) miRNA microarray reveals specific expression in the peripheral blood of glioblastoma patients. Int J Oncol 45(2):746–756

    Article  CAS  PubMed  Google Scholar 

  32. Zhi F, Shao N, Wang R et al (2015) Identification of 9 serum microRNAs as potential noninvasive biomarkers of human astrocytoma. Neuro Oncol 17(3):383–391

    Article  CAS  PubMed  Google Scholar 

  33. Regazzo G, Terrenato I, Spagnuolo M et al (2016) A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas. J Exp Clin Cancer Res 35(1):124–135

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tumilson CA, Lea RW, Alder JE et al (2014) Circulating MicroRNA biomarkers for glioma and predicting response to therapy. Mol Neurobiol 50(2):545–558

    Article  CAS  PubMed  Google Scholar 

  35. Feng Y-H, Tsao C-J (2016) Emerging role of microRNA-21 in cancer (Review). Biomed Rep 5:395–402

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65:6029–6033

    Article  CAS  PubMed  Google Scholar 

  37. D’Urso PI, D’Urso OF, Gianfreda CD et al (2015) miR-15b and miR-21 as circulating biomarkers for diagnosis of glioma. Curr Genomics 16:304–311

    Article  Google Scholar 

  38. Garofalo M, Quintavalle C, Romano G et al (2012) miR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med 12:27–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yu S, Liu X, Zhang Y et al (2016) Circulating microRNA124-3p, microRNA9-3p and microRNA196b-5p may be potential signatures for differential diagnosis of thyroid nodules. Oncotarget 7(51):84165–84177

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We wish to thank all patients and healthy controls who participated in this study, the neurosurgeons, nurses and staff of the Institute of Neurosurgery, the Colleagues and the personnel of Neuroradiology, of Pathology, of Neurology, of Oncology and Radiotherapy of the University Hospital of Verona for help in the organization of patient recruitment and blood collection, diagnosis and clinical management of the patients, Giuseppe Moretto and Alberto Beltramello for helpful discussions. AMB thanks Centro Piattaforme Tecnologiche (CPT), University of Verona for the use of the facility DLS and Riccardo Tognato for skilful assistance.

Funding

Supported by Brain Research Foundation, Verona, Italy.

Author information

Author notes

  1. Giulio Cabrini and Maria Cristina Dechecchi have contributed equally as senior authors.

Authors and Affiliations

  1. Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy

    Alessandra Santangelo, Anna Tamanini, Silvia Munari, Gianfranco Di Gennaro, Giuseppe Lippi, Giulio Cabrini & Maria Cristina Dechecchi

  2. Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    Pietro Imbrucè, Beatrice Gardenghi, Rina Agushi, Ilaria Scambi, Donatella Benati, Raffaella Mariotti, Andrea Sbarbati, Francesco Sala, Giuseppe Lippi & Giulio Cabrini

  3. Department of Biotechnology, University of Verona, Verona, Italy

    Alessandra Maria Bossi

  4. Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy

    Albino Eccher

  5. Neuroradiology Unit, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy

    Giuseppe Kenneth Ricciardi & Elisa Maria Ciceri

  6. Institute of Neurosurgery, University Hospital of Verona, Verona, Italy

    Laura Belli & Giampietro Pinna

  7. Laboratory of Molecular Pathology, Laboratory of Analyses, Department of Pathology and Diagnostics, University Hospital of Verona, Piazzale Stefani 1, 37126, Verona, Italy

    Maria Cristina Dechecchi

Authors
  1. Alessandra Santangelo
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  2. Pietro Imbrucè
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  3. Beatrice Gardenghi
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  4. Laura Belli
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  5. Rina Agushi
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  6. Anna Tamanini
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  7. Silvia Munari
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  8. Alessandra Maria Bossi
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  9. Ilaria Scambi
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  10. Donatella Benati
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  11. Raffaella Mariotti
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  12. Gianfranco Di Gennaro
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  13. Andrea Sbarbati
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  14. Albino Eccher
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  15. Giuseppe Kenneth Ricciardi
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  16. Elisa Maria Ciceri
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  17. Francesco Sala
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  18. Giampietro Pinna
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  19. Giuseppe Lippi
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  20. Giulio Cabrini
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  21. Maria Cristina Dechecchi
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Corresponding author

Correspondence to Maria Cristina Dechecchi.

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Santangelo, A., Imbrucè, P., Gardenghi, B. et al. A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker. J Neurooncol 136, 51–62 (2018). https://doi.org/10.1007/s11060-017-2639-x

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  • DOI: https://doi.org/10.1007/s11060-017-2639-x

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