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Horm Metab Res 2009; 41(6): 475-481
DOI: 10.1055/s-0029-1215593
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Analysis of Deregulated miRNAs is Helpful to Distinguish Poorly Differentiated Thyroid Carcinoma from Papillary Thyroid Carcinoma

S. Schwertheim 1 , S-Y. Sheu 1 [*] , K. Worm 1 , F. Grabellus 1 , K. W. Schmid 1 , 2
  • 1Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
  • 2Member of the West German Cancer Centre Essen (WTZE), Essen, Germany
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Publikationsverlauf

received 23.01.2009

accepted 09.03.2009

Publikationsdatum:
15. April 2009 (online)

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Abstract

Poorly differentiated thyroid carcinoma (PDTC) is defined as a malignant follicular cell derived neoplasm, both morphologically and biologically intermediate between well differentiated and anaplastic thyroid carcinoma (ATC). In the present study we investigated the expression levels of two distinct sets of miRNAs (‘set 1’: miRNA-146b, −181b, −21, −221, −222, all shown to be significantly upregulated in papillary thyroid carcinoma [PTC]; ‘set 2’: miRNA−30d, −125b, −26a, −30a−5p, and let7c, all downregulated in ATC) in a series of 15 PDTC (including 3 mixed PDTC/PTC), 9 ‘pure’ PTC, and 9 ATC. Compared to normal thyroid tissue all ‘set 1’ miRNAs were significantly upregulated in PTC (p<0.001); in ATC 4/5 miRNAs were upregulated (p<0.001) whereas in PDTC the expression levels of all 5 miRNAs did not differ significantly from normal thyroid. All miRNAs of ‘set 2’ were significantly upregulated in PTC (p<0.004) and downregulated in ATC (p<0.03); in PDTC only 3/5 were downregulated (p<0.011). All 10 miRNAs investigated differed significantly (p<0.003) between PTC and PDTC. In the histologically differentiated PTC compound of mixed PDTC/PTC cases, however, miRNA expression levels of all 10 miRNAs investigated lacked significant difference from those found in the PDTC compound, whereas 6/10 miRNAs differed significantly from ‘pure’ PTC. Our results indicate that analysis of distinct sets of miRNAs represent useful tools to distinguish PDTC from ‘pure’ PTC. Additionally our findings suggest that lack of deregulation of some miRNAs may select a subset of PTC prone to progression to PDTC.

Key words

miRNA - deregulation - poorly differentiated thyroid carcinoma - papillary thyroid carcinoma - anaplastic thyroid carcinoma

References

  • 1 DeLellis RA, Williams ED. Tumours of the Thyroid and Parathyroid. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. World Health Organization Classification of Tumours, Pathology & Genetics, Tumours of Endocrine Organs. Lyon: IARC Press 2004: 49-133
    Suche in Google Scholar
  • 2 Pilotti S, Collini P, Mariani L, Placucci M, Bongarzone I, Vigneri P, Cipriani S, Falcetta F, Miceli R, Pierotti MA, Rilke F. Insular carcinoma: a distinct de novo entity among follicular carcinomas of the thyroid gland.  Am J Surg Pathol. 1997;  21 1466-1473
    Suche in Google Scholar
  • 3 Carcangiu ML, Zampi G, Rosai J. Poorly differentiated (“insular”) thyroid carcinoma. A reinterpretation of Langhans’ “wuchernde Struma“.  Am J Surg Pathol. 1984;  8 655-668
    Suche in Google Scholar
  • 4 Sakamoto A. Definition of poorly differentiated carcinoma of the thyroid: the Japanese experience.  Endocr Pathol. 2004;  15 307-311
    Suche in Google Scholar
  • 5 Volante M, Collini P, Nikiforov YE, Sakamoto A, Kakudo K, Katoh R, Lloyd RV, LiVolsi VA, Papotti M, Sobrinho-Simoes M, Bussolati G, Rosai J. Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach.  Am J Surg Pathol. 2007;  31 1256-1264
    Suche in Google Scholar
  • 6 Cowland JB, Hother C, Gronbaek K. MicroRNAs and cancer.  APMIS. 2007;  115 1090-1106
    Suche in Google Scholar
  • 7 Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors.  Dev Biol. 2007;  302 1-12
    Suche in Google Scholar
  • 8 Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumorigenesis: a primer.  Am J Pathol. 2007;  171 728-738
    Suche in Google Scholar
  • 9 Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.  Proc Natl Acad Sci USA. 2002;  99 15524-15529
    Suche in Google Scholar
  • 10 Calin GA, Ferracin M, Cimmino A, Di LG, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia.  N Engl J Med. 2005;  353 1793-1801
    Suche in Google Scholar
  • 11 He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA, Liu CG, Franssila K, Suster S, Kloos RT, Croce CM, de la CA. The role of microRNA genes in papillary thyroid carcinoma.  Proc Natl Acad Sci USA. 2005;  102 19075-19080
    Suche in Google Scholar
  • 12 Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. MicroRNA gene expression deregulation in human breast cancer.  Cancer Res. 2005;  65 7065-7070
    Suche in Google Scholar
  • 13 Lu J, Getz G, Miska EA, varez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers.  Nature. 2005;  435 834-838
    Suche in Google Scholar
  • 14 Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK, Fedele V, Ginzinger D, Getts R, Haqq C. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies.  Mol Cancer. 2006;  5 24
    Suche in Google Scholar
  • 15 Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia.  Mol Cancer Res. 2003;  1 882-891
    Suche in Google Scholar
  • 16 Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues.  Oncogene. 2006;  25 2537-2545
    Suche in Google Scholar
  • 17 Pallante P, Visone R, Ferracin M, Ferraro A, Berlingieri MT, Troncone G, Chiappetta G, Liu CG, Santoro M, Negrini M, Croce CM, Fusco A. MicroRNA deregulation in human thyroid papillary carcinomas.  Endocr Relat Cancer. 2006;  13 497-508
    Suche in Google Scholar
  • 18 Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.  Cancer Res. 2004;  64 3753-3756
    Suche in Google Scholar
  • 19 Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A, Volinia S, Coluzzi S, Leone V, Borbone E, Liu CG, Petrocca F, Troncone G, Calin GA, Scarpa A, Colato C, Tallini G, Santoro M, Croce CM, Fusco A. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas.  Oncogene. 2007;  26 7590-7595
    Suche in Google Scholar
  • 20 Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets.  Proc Natl Acad Sci U S A. 2006;  103 2257-2261
    Suche in Google Scholar
  • 21 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 1600-1608
    Suche in Google Scholar
  • 22 Tetzlaff MT, Liu A, Xu X, Master SR, Baldwin DA, Tobias JW, LiVolsi VA, Baloch ZW. Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues.  Endocr Pathol. 2007;  18 163-173
    Suche in Google Scholar
  • 23 Chen YT, Kitabayashi N, Zhou XK, Fahey III TJ, Scognamiglio T. MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma.  Mod Pathol. 2008;  21 1139-1146
    Suche in Google Scholar
  • 24 Lehmann U, Kreipe H. Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies.  Methods. 2001;  25 409-418
    Suche in Google Scholar
  • 25 Specht K, Richter T, Muller U, Walch A, Werner M, Hofler H. Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue.  Am J Pathol. 2001;  158 419-429
    Suche in Google Scholar
  • 26 Sheu SY, Schwertheim S, Worm K, Grabellus F, Schmid KW. Diffuse sclerosing variant of papillary thyroid carcinoma: lack of BRAF mutation but occurrence of RET/PTC rearrangements.  Mod Pathol. 2007;  20 779-787
    Suche in Google Scholar
  • 27 Nikiforov YE, Nikiforova MN, Gnepp DR, Fagin JA. Prevalence of mutations of ras and p53 in benign and malignant thyroid tumors from children exposed to radiation after the Chernobyl nuclear accident.  Oncogene. 1996;  13 687-693
    Suche in Google Scholar
  • 28 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.  Methods. 2001;  25 402-408
    Suche in Google Scholar
  • 29 Sakamoto A, Kasai N, Sugano H. Poorly differentiated carcinoma of the thyroid. A clinicopathologic entity for a high-risk group of papillary and follicular carcinomas.  Cancer. 1983;  52 1849-1855
    Suche in Google Scholar
  • 30 Hiltzik D, Carlson DL, Tuttle RM, Chuai S, Ishill N, Shaha A, Shah JP, Singh B, Ghossein RA. Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients.  Cancer. 2006;  106 1286-1295
    Suche in Google Scholar
  • 31 Volante M, Landolfi S, Chiusa L, Palestini N, Motta M, Codegone A, Torchio B, Papotti MG. Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns: a clinicopathologic study of 183 patients.  Cancer. 2004;  100 950-957
    Suche in Google Scholar
  • 32 Sheu S, Grabellus F, Schwertheim S, Handke S, Worm K, Schmid KW. Lack of correlation between BRAF V600E mutational stuatus and the expression profile of a distinct set of miRNAs in papillary thyroid carcinoma.  Horm Metab Res. 2009;  41
    Suche in Google Scholar
  • 33 Mayr B, Brabant G, Goretzki P, Ruschoff J, Dietmaier W, Dralle H. ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?.  J Clin Endocrinol Metab. 1997;  82 1306-1307
    Suche in Google Scholar
  • 34 Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms?.  J Pathol. 1998;  185 71-78
    Suche in Google Scholar
  • 35 Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, Carcangiu ML, Fusco A. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes.  Clin Cancer Res. 1998;  4 287-294
    Suche in Google Scholar
  • 36 Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J, Benz CC. Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells.  Oncogene. 2008;  27 5643-5647
    Suche in Google Scholar
  • 37 Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.  Proc Natl Acad Sci USA. 2006;  103 12481-12486
    Suche in Google Scholar
  • 38 Waes C Van. Nuclear factor-kappaB in development, prevention, and therapy of cancer.  Clin Cancer Res. 2007;  13 1076-1082
    Suche in Google Scholar
  • 39 Mercurio F, Manning AM. NF-kappaB as a primary regulator of the stress response.  Oncogene. 1999;  18 6163-6171
    Suche in Google Scholar
  • 40 Visconti R, Cerutti J, Battista S, Fedele M, Trapasso F, Zeki K, Miano MP, de NF, Casalino L, Curcio F, Santoro M, Fusco A. Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkappaB p65 protein expression.  Oncogene. 1997;  15 1987-1994
    Suche in Google Scholar
  • 41 Chiappetta G, Ferraro A, Vuttariello E, Monaco M, Galdiero F, De SV, Califano D, Pallante P, Botti G, Pezzullo L, Pierantoni GM, Santoro M, Fusco A. HMGA2 mRNA expression correlates with the malignant phenotype in human thyroid neoplasias.  Eur J Cancer. 2008;  44 1015-1021
    Suche in Google Scholar
  • 42 Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas.  J Clin Endocrinol Metab. 2003;  88 5399-5404
    Suche in Google Scholar
  • 43 Basolo F, Pisaturo F, Pollina LE, Fontanini G, Elisei R, Molinaro E, Iacconi P, Miccoli P, Pacini F. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression.  Thyroid. 2000;  10 19-23
    Suche in Google Scholar
  • 44 Garcia-Rostan G, Zhao H, Camp RL, Pollan M, Herrero A, Pardo J, Wu R, Carcangiu ML, Costa J, Tallini G. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer.  J Clin Oncol. 2003;  21 3226-3235
    Suche in Google Scholar
  • 45 Motoi N, Sakamoto A, Yamochi T, Horiuchi H, Motoi T, Machinami R. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin.  Pathol Res Pract. 2000;  196 1-7
    Suche in Google Scholar
  • 46 Vitagliano D, Portella G, Troncone G, Francione A, Rossi C, Bruno A, Giorgini A, Coluzzi S, Nappi TC, Rothstein JL, Pasquinelli R, Chiappetta G, Terracciano D, Macchia V, Melillo RM, Fusco A, Santoro M. Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas.  Oncogene. 2006;  25 5467-5474
    Suche in Google Scholar
  • 47 Broecker-Preuss M, Sheu SY, Worm K, Feldkamp J, Witte J, Scherbaum WA, Mann K, Schmid KW, Schott M. Expression and mutation analysis of the tyrosine kinase c-kit in poorly differentiated and anaplastic thyroid carcinoma.  Horm Metab Res. 2008;  40 685-691
    Suche in Google Scholar
  • 48 Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW, Tallini G, Kroll TG, Nikiforov YE. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.  J Clin Endocrinol Metab. 2003;  88 2318-2326
    Suche in Google Scholar
  • 49 Vasko V, Ferrand M, Di CJ, Carayon P, Henry JF, de MC. Specific pattern of RAS oncogene mutations in follicular thyroid tumors.  J Clin Endocrinol Metab. 2003;  88 2745-2752
    Suche in Google Scholar
  • 50 Zhu Z, Gandhi M, Nikiforova MN, FISCHER AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations.  Am J Clin Pathol. 2003;  120 71-77
    Suche in Google Scholar
  • 51 Benvenga S. Update on thyroid cancer.  Horm Metab Res. 2008;  40 323-328
    Suche in Google Scholar

1 These authors contributed equally to this work.

Correspondence

K. W. SchmidMD, MRCPath 

Institute of Pathology and Neuropathology

University Hospital of Essen

University of Duisburg-Essen

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Germany

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