Pituitary

, Volume 18, Issue 5, pp 710–721 | Cite as

MicroRNA involvement in a metastatic non-functioning pituitary carcinoma

  • Zhenqing Wei
  • Cuiqi Zhou
  • Mei Liu
  • Yong Yao
  • Jian Sun
  • Jianqi Xiao
  • Wenbin Ma
  • Huijuan Zhu
  • Renzhi Wang
Article

Abstract

Purpose

Pituitary carcinomas are extremely rare neoplasms, and molecular events leading to malignant pituitary transformation are largely unknown. Enhanced understanding of molecular mechanisms driving malignant pituitary progression would be beneficial for pituitary carcinoma diagnosis and treatment.

Methods

Differential microRNA expression in paired primary and metastatic pituitary carcinoma specimens were detected using high-throughput human microRNA microarrays and TaqMan microRNA arrays. Three of significantly deregulated miRNAs were further confirmed using quantitative real-time PCR in the metastatic carcinoma, six atypical pituitary adenomas and eight typical pituitary adenomas. Target genes of microRNAs were bioinformatically predicated and verified in vitro by Western blotting and real-time PCR and in vivo by immunohistochemistry respectively.

Results

We present a case of a 50-year-old woman harboring non-functioning pituitary carcinoma with multiple intracranial metastases, and identified up-regulation of miR-20a, miR-106b and miR-17-5p in the metastatic carcinoma as compared to the primary neoplasm. Furthermore, miR-20a and miR-17-5p were increased in the metastatic carcinoma and six atypical pituitary adenomas as compared to eight typical pituitary adenomas as measured by quantitative real-time PCR. Both PTEN and TIMP2 were bioinformatically predicated and confirmed in vitro as target genes of these three microRNAs. As semi-quantified by immunohistochemistry, PTEN was absent and TIMP2 was decreased in the metastatic pituitary carcinoma as compared to pituitary adenomas.

Conclusions

Our results suggest microRNA involvement in malignant pituitary progression, whereby increased miR-20a, miR-106b and miR-17-5p promote metastasis by attenuating PTEN and TIMP2 in pituitary carcinoma.

Keywords

Carcinoma Pituitary MicroRNA Metastasis 

References

  1. 1.
    Lloyd RV, Kovacs K, Young WF Jr, Farrel WE, Asa SL, Trouillas J et al (2004) Pituitary tumors: introduction. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) Tumors of pituitary, chapter 1. Pathology and genetics of tumours of endocrine organs. World Health Organization Classification of Tumours. IARC Press, LyonGoogle Scholar
  2. 2.
    Amar AP, Hinton DR, Krieger MD, Weiss MH (1999) Invasive pituitary adenomas: significance of proliferation parameters. Pituitary 2:117–122CrossRefPubMedGoogle Scholar
  3. 3.
    Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ et al (1996) Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38(99–106):106–107Google Scholar
  4. 4.
    Kaltsas GA, Grossman AB (1998) Malignant pituitary tumours. Pituitary 1:69–81CrossRefPubMedGoogle Scholar
  5. 5.
    Ragel BT, Couldwell WT (2004) Pituitary carcinoma: a review of the literature. Neurosurg Focus 16:E7CrossRefPubMedGoogle Scholar
  6. 6.
    Sironi M, Cenacchi G, Cozzi L, Tonnarelli G, Iacobellis M, Trere D et al (2002) Progression on metastatic neuroendocrine carcinoma from a recurrent prolactinoma: a case report. J Clin Pathol 55:148–151PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefPubMedGoogle Scholar
  8. 8.
    Cuellar TL, McManus MT (2005) MicroRNAs and endocrine biology. J Endocrinol 187:327–332CrossRefPubMedGoogle Scholar
  9. 9.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866CrossRefPubMedGoogle Scholar
  10. 10.
    Ma L, Weinberg RA (2008) MicroRNAs in malignant progression. Cell Cycle 7:570–572CrossRefPubMedGoogle Scholar
  11. 11.
    Butz H, Liko I, Czirjak S, Igaz P, Korbonits M, Racz K et al (2011) MicroRNA profile indicates downregulation of the TGFbeta pathway in sporadic non-functioning pituitary adenomas. Pituitary 14:112–124CrossRefPubMedGoogle Scholar
  12. 12.
    Cheunsuchon P, Zhou Y, Zhang X, Lee H, Chen W, Nakayama Y et al (2011) Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas. Am J Pathol 179:2120–2130PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    D’Angelo D, Palmieri D, Mussnich P, Roche M, Wierinckx A, Raverot G 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–E1138CrossRefPubMedGoogle Scholar
  14. 14.
    Leone V, Langella C, D’Angelo D, Mussnich P, Wierinckx A, Terracciano L et al (2014) Mir-23b and miR-130b expression is downregulated in pituitary adenomas. Mol Cell Endocrinol 390:1–7CrossRefPubMedGoogle Scholar
  15. 15.
    Palmieri D, D’Angelo D, Valentino T, De Martino I, Ferraro A, Wierinckx A et al (2012) Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis. Oncogene 31:3857–3865CrossRefPubMedGoogle Scholar
  16. 16.
    Palumbo T, Faucz FR, Azevedo M, Xekouki P, Iliopoulos D, Stratakis CA (2013) Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway. Oncogene 32:1651–1659PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Stilling G, Sun Z, Zhang S, Jin L, Righi A, Kovacs G, Korbonits M, Scheithauer BW, Kovacs K, Lloyd RV (2010) MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and -493 in pituitary carcinomas. Endocrine 38:67–75CrossRefPubMedGoogle Scholar
  18. 18.
    Trivellin G, Butz H, Delhove J, Igreja S, Chahal HS, Zivkovic V, McKay T, Patocs A, Grossman AB, Korbonits M (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–E719CrossRefPubMedGoogle Scholar
  19. 19.
    Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7:257–266CrossRefPubMedGoogle Scholar
  20. 20.
    Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT et al (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33:e179PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  22. 22.
    Feng ZZ, Chen JW, Yang ZR, Lu GZ, Cai ZG (2012) Expression of PTTG1 and PTEN in endometrial carcinoma: correlation with tumorigenesis and progression. Med Oncol 29:304–310CrossRefPubMedGoogle Scholar
  23. 23.
    Rhodes A, Jasani B, Balaton AJ, Miller KD (2000) Immunohistochemical demonstration of oestrogen and progesterone receptors: correlation of standards achieved on in house tumours with that achieved on external quality assessment material in over 150 laboratories from 26 countries. J Clin Pathol 53:292–301PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Lee YS, Dutta A (2009) MicroRNAs in cancer. Annu Rev Pathol 4:199–227PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Gadelha MR, Kasuki L, Denes J, Trivellin G, Korbonits M (2013) MicroRNAs: suggested role in pituitary adenoma pathogenesis. J Endocrinol Invest 36:889–895CrossRefPubMedGoogle Scholar
  26. 26.
    Fan X, Liu Y, Jiang J, Ma Z, Wu H, Liu T et al (2010) miR-20a promotes proliferation and invasion by targeting APP in human ovarian cancer cells. Acta Biochim Biophys Sin 42:318–324CrossRefPubMedGoogle Scholar
  27. 27.
    Huang G, Nishimoto K, Zhou Z, Hughes D, Kleinerman ES (2012) miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression. Cancer Res 72:908–916PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Chang Y, Liu C, Yang J, Liu G, Feng F, Tang J et al (2013) MiR-20a triggers metastasis of gallbladder carcinoma. J Hepatol 59:518–527CrossRefPubMedGoogle Scholar
  29. 29.
    Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM et al (2010) Identification of the miR-106b ~ 25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal 3:a29CrossRefGoogle Scholar
  30. 30.
    Yau WL, Lam CS, Ng L, Chow AK, Chan ST, Chan JY et al (2013) Over-expression of miR-106b promotes cell migration and metastasis in hepatocellular carcinoma by activating epithelial-mesenchymal transition process. PLoS one 8:e57882PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Fang L, Li H, Wang L, Hu J, Jin T, Wang J et al (2014) MicroRNA-17-5p promotes chemotherapeutic drug resistance and tumour metastasis of colorectal cancer by repressing PTEN expression. Oncotarget 5:2974–2987PubMedCentralPubMedGoogle Scholar
  32. 32.
    Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20CrossRefPubMedGoogle Scholar
  34. 34.
    Cantley LC, Neel BG (1999) New insights into tumor suppression: pTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Mayo LD, Donner DB (2002) The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci 27:462–467CrossRefPubMedGoogle Scholar
  36. 36.
    Yamada KM, Araki M (2001) Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci 114:2375–2382PubMedGoogle Scholar
  37. 37.
    Zhang LL, Liu J, Lei S, Zhang J, Zhou W, Yu HG (2014) PTEN inhibits the invasion and metastasis of gastric cancer via downregulation of FAK expression. Cell Signal 26:1011–1020CrossRefPubMedGoogle Scholar
  38. 38.
    Ma F, Zhang J, Zhong L, Wang L, Liu Y, Wang Y et al (2014) Upregulated microRNA-301a in breast cancer promotes tumor metastasis by targeting PTEN and activating Wnt/beta-catenin signaling. Gene 535:191–197CrossRefPubMedGoogle Scholar
  39. 39.
    Wong GS, Rustgi AK (2013) Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis. Br J Cancer 108:755–761PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Danilewicz M, Sikorska B, Wagrowska-Danilewicz M (2003) Prognostic significance of the immunoexpression of matrix metalloproteinase MMP2 and its inhibitor TIMP2 in laryngeal cancer. Med Sci Monit 9:T42–T47Google Scholar
  41. 41.
    Kazes I, Elalamy I, Sraer JD, Hatmi M, Nguyen G (2000) Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation. Blood 96:3064–3069PubMedGoogle Scholar
  42. 42.
    DeClerck YA, Perez N, Shimada H, Boone TC, Langley KE, Taylor SM (1992) Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52:701–708PubMedGoogle Scholar
  43. 43.
    Li H, Lindenmeyer F, Grenet C, Opolon P, Menashi S, Soria C et al (2001) AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. Hum Gene Ther 12:515–526CrossRefPubMedGoogle Scholar
  44. 44.
    Nuovo GJ, MacConnell PB, Simsir A, Valea F, French DL (1995) Correlation of the in situ detection of polymerase chain reaction-amplified metalloproteinase complementary DNAs and their inhibitors with prognosis in cervical carcinoma. Cancer Res 55:267–275PubMedGoogle Scholar
  45. 45.
    Scheithauer BW, Kovacs KT, Laws EJ, Randall RV (1986) Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg 65:733–744CrossRefPubMedGoogle Scholar
  46. 46.
    Scheithauer BW, Kurtkaya-Yapicier O, Kovacs KT, Young WJ, Lloyd RV (2005) Pituitary carcinoma: a clinicopathological review. Neurosurgery 56:1066–1074PubMedGoogle Scholar
  47. 47.
    Kontogeorgos G (2005) Classification and pathology of pituitary tumors. Endocrine 28:27–35CrossRefPubMedGoogle Scholar
  48. 48.
    Pasquel FJ, Vincentelli C, Brat DJ, Oyesiku NM, Ioachimescu AG (2013) Pituitary carcinoma in situ. Endocr Pract 19:e69–e73CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zhenqing Wei
    • 1
    • 7
  • Cuiqi Zhou
    • 2
    • 8
  • Mei Liu
    • 3
  • Yong Yao
    • 1
  • Jian Sun
    • 4
  • Jianqi Xiao
    • 5
  • Wenbin Ma
    • 1
  • Huijuan Zhu
    • 6
  • Renzhi Wang
    • 1
    • 8
  1. 1.Department of Neurosurgery, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingPeople’s Republic of China
  2. 2.Department of MedicineCedars-Sinai Medical CenterLos AngelesUSA
  3. 3.Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Institute & Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingPeople’s Republic of China
  4. 4.Department of Pathology, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingPeople’s Republic of China
  5. 5.Department of NeurosurgeryThe First Hospital of QiqiharQiqiharPeople’s Republic of China
  6. 6.Department of Endocrinology, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingPeople’s Republic of China
  7. 7.Department of NeurosurgeryThe First Hospital Affiliated to Dalian Medical UniversityDalianPeople’s Republic of China
  8. 8.Joint Pituitary Research Center of CSMC & PUMCH, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingPeople’s Republic of China

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