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Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas

Oncogene volume 29, pages 4237–4244 (2010)Cite this article

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Abstract

Anaplastic thyroid carcinomas (ATCs) arise from epithelial thyroid cells by mesenchymal de-/transdifferentiation and rapidly invade the adjacent tissue. Specific microRNA signatures were suggested to distinguish ATCs from normal thyroid tissue and other thyroid carcinomas of follicular origin. Whether distinct microRNA patterns correlate with de-/transdifferentiation and invasion of ATCs remained elusive. We identified two significantly decreased microRNA families that unambiguously distinguish ATCs from papillary and follicular thyroid carcinomas: miR-200 and miR-30. Expression of these microRNAs in mesenchymal ATC-derived cells reduced their invasive potential and induced mesenchymal–epithelial transition (MET) by regulating the expression of MET marker proteins. Supporting the role of transforming growth factor (TGF)β signaling in modulating MET/epithelial–mesenchymal transition (EMT), expression of SMAD2 and TGFBR1, upregulated in most primary ATCs, was controlled by members of the miR-30 and/or miR-200 families in ATC-derived cells. Inhibition of TGFβ receptor 1 (TGFBR1) in these cells induced MET and reduction of prometastatic miR-21, but caused an increase of the miR-200 family. These findings identify altered microRNA signatures as potent markers for ATCs that promote de-/transdifferentiation (EMT) and invasion of these neoplasias. Hence, TGFBR1 inhibition could have a significant potential for the treatment of ATCs and possibly other invasive tumors.

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References

  • Brabant G, Hoang-Vu C, Cetin Y, Dralle H, Scheumann G, Molne J et al (1993). E-cadherin: a differentiation marker in thyroid malignancies. Cancer Res 53: 4987–4993.

    CAS  PubMed  Google Scholar 

  • Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF et al (2008). A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68: 7846–7854.

    Article  CAS  Google Scholar 

  • Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A et al. (2008). Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47: 897–907.

    Article  CAS  Google Scholar 

  • Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S et al. (2008). A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9: 582–589.

    Article  CAS  Google Scholar 

  • Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A et al. (1996). TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86: 531–542.

    Article  CAS  Google Scholar 

  • Davis BN, Hilyard AC, Lagna G, Hata A . (2008). SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454: 56–61.

    Article  CAS  Google Scholar 

  • Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al. (2008). The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10: 593–601.

    Article  CAS  Google Scholar 

  • Guzinska-Ustymowicz K, Kemona A . (2005). Transforming growth factor beta can be a parameter of aggressiveness of pT1 colorectal cancer. World J Gastroenterol 11: 1193–1195.

    Article  CAS  Google Scholar 

  • He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S et al. (2005). The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 102: 19075–19080.

    Article  CAS  Google Scholar 

  • Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH et al. (2009). Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucl Acids Res 37: 1672–1681.

    Article  CAS  Google Scholar 

  • Kondo T, Ezzat S, Asa SL . (2006). Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6: 292–306.

    Article  CAS  Google Scholar 

  • Mercatelli N, Coppola V, Bonci D, Miele F, Costantini A, Guadagnoli M et al. (2008). The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. PLoS One 3: e4029.

    Article  Google Scholar 

  • Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE . (2008). MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab 93: 1600–1608.

    Article  CAS  Google Scholar 

  • Pallante P, Visone R, Ferracin M, Ferraro A, Berlingieri MT, Troncone G et al. (2006). MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer 13: 497–508.

    Article  CAS  Google Scholar 

  • Park SM, Gaur AB, Lengyel E, Peter ME . (2008). The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22: 894–907.

    Article  CAS  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P . (2005). Global Cancer Statistics, 2002. CA Cancer J Clin 55: 74–108.

    Article  Google Scholar 

  • Piek E, Moustakas A, Kurisaki A, Heldin CH, ten Dijke P . (1999). TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112 (Part 24): 4557–4568.

    CAS  PubMed  Google Scholar 

  • Resnick MB, Schacter P, Finkelstein Y, Kellner Y, Cohen O . (1998). Immunohistochemical analysis of p27/kip1 expression in thyroid carcinoma. Mod Pathol 11: 735–739.

    CAS  PubMed  Google Scholar 

  • Rocha AS, Soares P, Fonseca E, Cameselle-Teijeiro J, Oliveira MC, Sobrinho-Simoes M . (2003). E-cadherin loss rather than beta-catenin alterations is a common feature of poorly differentiated thyroid carcinomas. Histopathology 42: 580–587.

    Article  CAS  Google Scholar 

  • Safina A, Vandette E, Bakin AV . (2007). ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 26: 2407–2422.

    Article  CAS  Google Scholar 

  • Schwertheim S, Sheu SY, Worm K, Grabellus F, Schmid KW . (2009). Analysis of deregulated miRNAs is helpful to distinguish poorly differentiated thyroid carcinoma from papillary thyroid carcinoma. Horm Metab Res 41: 475–481.

    Article  CAS  Google Scholar 

  • Shao ES, Lin L, Yao Y, Boström KI . (2009). Expression of vascular endothelial growth factor is coordinately regulated by the activin-like kinase receptors 1 and 5 in endothelial cells. Blood 114: 2197–2206.

    Article  CAS  Google Scholar 

  • Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S et al. (2007). Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci USA 104: 2803–2808.

    Article  CAS  Google Scholar 

  • Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A et al. (2007). Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 26: 7590–7595.

    Article  CAS  Google Scholar 

  • Weber F, Teresi RE, Broelsch CE, Frilling A, Eng C . (2006). A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma. J Clin Endocrinol Metab 91: 3584–3591.

    Article  CAS  Google Scholar 

  • Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY . (2008). MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 18: 350–359.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by DFG and BMBF (FKZ 01ZZ0404) funding to Stefan Hüttelmaier.

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Martin Luther University Halle-Wittenberg, Halle, Germany

    J Braun & S Hüttelmaier

  2. Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany

    C Hoang-Vu & H Dralle

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  1. J Braun
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  2. C Hoang-Vu
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  3. H Dralle
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  4. S Hüttelmaier
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Correspondence to S Hüttelmaier.

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Braun, J., Hoang-Vu, C., Dralle, H. et al. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene 29, 4237–4244 (2010). https://doi.org/10.1038/onc.2010.169

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