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MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior

Abstract

Background

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs).

Purpose

In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features.

Methods

Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation.

Results

All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and ‘atypical’ morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043).

Conclusions

In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

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References

  1. 1.

    Daly AF, Burlacu MC, Livadariu E, Beckers A (2007) The epidemiology and management of pituitary incidentalomas. Horm Res 68:195–198. https://doi.org/10.1159/000110624

  2. 2.

    Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr (2011) Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg 114:336–344. https://doi.org/10.3171/2010.8.JNS10290

  3. 3.

    Raverot G, Burman P, McCormack A et al (2018) European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endcrinol 178:1–24. https://doi.org/10.1530/EJE-17-0796

  4. 4.

    Caro DBD, Solari D, Pagliuca F et al (2016) Atypical pituitary adenomas: clinical characteristics and role of Ki-67 and p53 in prognostic and therapeutic evaluation. A series of 50 patients. Neurosurg Rev 40:105–114. https://doi.org/10.1007/s10143-016-0740-9

  5. 5.

    Miermeister CP, Petersenn S, Buchfelder M et al (2015) Histological criteria for atypical pituitary adenomas—data from the German pituitary adenoma registry suggests modifications. Acta Neuropathol Commun 3:50. https://doi.org/10.1186/s40478-015-0229-8

  6. 6.

    Saeger W, Petersenn S, Schöfl C et al (2016) Emerging histopathological and genetic parameters of pituitary adenomas: clinical impact and recommendation for future WHO classification. Endocr Pathol 27:115–122. https://doi.org/10.1007/s12022-016-9419-6

  7. 7.

    Robertson AM, Heaney AP (2016) Molecular markers in pituitary tumors. Curr Opin Endocrinol Diabetes Obes 23:324–330. https://doi.org/10.1097/MED.0000000000000266

  8. 8.

    Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355. https://doi.org/10.1038/nature02871

  9. 9.

    Bueno MJ, Malumbres M (2011) MicroRNAs and the cell cycle. Biochim Biophys Acta 1812:592–601. https://doi.org/10.1016/j.bbadis.2011.02.002

  10. 10.

    Zhang B, Pan X, Cobb GP, Anderson TA (2007) MicroRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12. https://doi.org/10.1016/j.ydbio.2006.08.028

  11. 11.

    Peng Y, Croce CM (2016) The role of MicroRNAs in human cancer. Signal Transduct Target Ther 1:15004. https://doi.org/10.1038/sigtrans.2015.4

  12. 12.

    Tan W, Liu B, Qu S, Liang G, Luo W, Gong C (2018) MicroRNAs and cancer: key paradigms in molecular therapy. Oncol Lett 15:2735–2742. https://doi.org/10.3892/ol.2017.7638

  13. 13.

    Feng Y, Mao ZG, Wang X et al (2018) MicroRNAs and target genes in pituitary adenomas. Horm Metab Res 50:179–192. https://doi.org/10.1055/s-0043-123763

  14. 14.

    Ruggeri RM, Costa G, Simone A et al (2012) Cell proliferation parameters and apoptosis indices in pituitary macroadenomas. J Endocrinol Invest 35:473–478. https://doi.org/10.3275/7905

  15. 15.

    Bustin SA, Benes V, Garson J (2013) The need for transparency and good practices in the qPCR literature. Nat Methods 10:1063–1067. https://doi.org/10.1038/nmeth.2697

  16. 16.

    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45. https://doi.org/10.1093/nar/29.9.e45

  17. 17.

    Musolino C, Oteri G, Allegra A et al (2018) Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw. Ann Hematol 97:1259–1269. https://doi.org/10.1007/s00277-018-3296-7

  18. 18.

    Zhang W, Zang J, Jing X et al (2014) Identification of candidate miRNA biomarkers from miRNA regulatory network with application to prostate cancer. J Transl Med 12:66. https://doi.org/10.1186/1479-5876-12-66

  19. 19.

    Zhao Y, Yan M, Yun Y et al (2017) MicroRNA-455-3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. Oncol Rep 37:2449–2458. https://doi.org/10.3892/or.2017.5502

  20. 20.

    Bottoni A, Ferracin M, Tagliati F et al (2007) Identification of differentially expressed microRNAs by microarray: a possible role for microRNA genes in pituitary adenomas. J Cell Physiol 210:370–377. https://doi.org/10.1002/jcp.20832

  21. 21.

    D’Angelo D, Palmieri D, Mussnich P et al (2012) Altered microRNA expression profile in human pituitary GH adenomas: down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1. J Clin Endocrinol Metab 97:E1128–E1138. https://doi.org/10.1210/jc.2011-3482

  22. 22.

    Gadelha MR, Kasuki L, Dènes J, Trivellin G, Korbonits M (2013) MicroRNAs: suggested role in pituitary adenoma pathogenesis. J. Endocrinol. Invest 36:889–895. https://doi.org/10.1007/BF03346759

  23. 23.

    Mao ZG, He DS, Zhou J et al (2010) Differential expression of microRNAs in GH-secreting pituitary adenomas. Diagn Pathol 5:79. https://doi.org/10.1186/1746-1596-5-79

  24. 24.

    Trivellin G, Butz H, Delhove J et al (2012) MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro. Am J Physiol Endocrinol Metab 303:E708–E719. https://doi.org/10.1152/ajpendo.00546.2011

  25. 25.

    Williams M, Cheng YY, Blenkiron C, Reid G (2017) Exploring mechanisms of MicroRNA downregulation in cancer. MicroRNA 6:2–16. https://doi.org/10.2174/2211536605666161208154633

  26. 26.

    Robbins HL, Hague A (2016) The PI3K/Akt pathway in tumors of endocrine tissues. Front Endocrinol (Lausanne) 6:188. https://doi.org/10.3389/fendo.2015.00188

  27. 27.

    Trovato M, Torre ML, Ragonese M et al (2013) HGF/c-met system targeting PI3K/AKT and STAT3/phosphorylated-STAT3 pathways in pituitary adenomas: an immunohistochemical characterization in view of targeted therapies. Endocrine 44:735–743. https://doi.org/10.1007/s12020-013-9950-x

  28. 28.

    Cannavo S, Trimarchi F, Ferraù F (2017) Acromegaly, genetic variants of the aryl hydrocarbon receptor pathway and environmental burden. Mol Cell Endocrinol 457:81–88. https://doi.org/10.1016/j.mce.2016.12.019

  29. 29.

    Cannavo S, Ragonese M, Puglisi S et al (2016) Acromegaly is more severe in patients with AHR or AIP gene variants living in highly polluted areas. J Clin Endocrinol Metab 101:1872–1879. https://doi.org/10.1210/jc.2015-4191

  30. 30.

    Ferraù F, Romeo PD, Puglisi S et al (2019) GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly. J Endocrinol Invest 42:825–831. https://doi.org/10.1007/s40618-018-0988-8

  31. 31.

    Cannavo S, Ferrau F, Ragonese M et al (2014) Increased frequency of the rs2066853 variant of aryl hydrocarbon receptor gene in patients with acromegaly. Clin Endocrinol (Oxf) 81:249–253. https://doi.org/10.1111/cen.12424

  32. 32.

    Zhenye L, Chuzhong L, Youtu W (2014) The expression of TGF-β1, Smad3, phospho-Smad3 and Smad7 is correlated with the development and invasion of nonfunctioning pituitary adenomas. J Transl Med 12:71. https://doi.org/10.1186/1479-5876-12-71

  33. 33.

    Tzeng HT, Wang YC (2016) Rab-mediated vesicle trafficking in cancer. J Biomed Sci 23:70. https://doi.org/10.1186/s12929-016-0287-7

  34. 34.

    Vazquez-Martinez R, Martinez-Fuentes AJ, Pulido MR et al (2008) Rab18 is reduced in pituitary tumors causing acromegaly and its overexpression reverts growth hormone hypersecretion. J Clin Endocrinol Metab 93:2269–2276. https://doi.org/10.1210/jc.2007-1893

  35. 35.

    He Z, Chen L, Hu X, Tang J et al (2019) Next-generation sequencing of microRNAs reveals a unique expression pattern in different types of pituitary adenomas. Endocr J 66:709–722. https://doi.org/10.1507/endocrj.EJ18-0487

  36. 36.

    Fukumoto I, Hanazawa T, Kinoshita T et al (2015) MicroRNA expression signature of oral squamous cell carcinoma: functional role of microRNA-26a/b in the modulation of novel cancer pathways. Br J Cancer 112:891–900. https://doi.org/10.1038/bjc.2015.19

  37. 37.

    Miyamoto K, Seki N, Matsushita R, Yonemori M et al (2016) Tumour-suppressive miRNA-26a-5p and miR-26b-5p inhibit cell aggressiveness by regulating PLOD2 in bladder cancer. Br J Cancer 115:354–363. https://doi.org/10.1038/bjc.2015.19

  38. 38.

    Li Y, Sun Z, Liu B, Shan Y, Zhao L, Jia L (2017) Tumor-suppressive miR-26a and miR-26b inhibit cell aggressiveness by regulating FUT4 in colorectal cancer. Cell Death Dis 8:e2892. https://doi.org/10.1038/cddis.2017.281

  39. 39.

    Liu YH, Li B, Meng FG, Qiu L (2017) MiR-508-5p is a prognostic marker and inhibits cell proliferation and migration in glioma. Eur Rev Med Pharmacol Sci 21:76–81

  40. 40.

    Chan CK, Pan Y, Nyberg K et al (2016) Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour. Open Biol 6:160275. https://doi.org/10.1098/rsob.160275

  41. 41.

    Jia Z, Wang K, Wang G, Zhang A, Pu P (2013) MiR-30a-5p antisense oligonucleotide suppresses glioma cell growth by targeting PLoS ONE 8: e55008. 10.1371/journal.pone.0055008.

  42. 42.

    Ma Y, Zhang P, Yang J, Liu Z, Yang Z, Qin H (2012) Candidate microRNA biomarkers in human colorectal cancer: systematic review profiling studies and experimental validation. Int J Cancer 130:2077–2087. https://doi.org/10.1002/ijc.26232

  43. 43.

    Ruan P, Tao Z, Tan A (2018) Low expression of miR-30a-5p induced the proliferation and invasion of oral cancer via promoting the expression of FAP. Biosci Rep 38(1). 10.1042/BSR20171027.

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Author information

TMV, FA conceived experimental design, performed lab experiments and data analysis and wrote the manuscript; FP, RO set up experimental protocol and performed lab experiments. FF conceived study design, collected clinical and pathological data and revised the manuscript; GG, MLT, MR, ORC, FS followed up patients and collected clinical, neuroradiological and pathological data; SC conceived study design and revised the manuscript; RMR supported data analysis, wrote and revised the manuscript; MA supported data analysis and revised the manuscript; FFA, FE, AlAs collected tissue samples; AA performed statistical analysis.

Correspondence to F. Ferraù.

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Cite this article

Vicchio, T.M., Aliquò, F., Ruggeri, R.M. et al. MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior . J Endocrinol Invest (2020). https://doi.org/10.1007/s40618-019-01178-4

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Keywords

  • Pituitary tumor
  • MicroRNA
  • MiRNA
  • Biomarkers
  • Aggressive pituitary tumor