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Changes in the expression pattern of apoptotic molecules (galectin-3, Bcl-2, Bax, survivin) during progression of thyroid malignancy and their clinical significance

Änderungen im Expressionsmuster von apoptotischen Molekülen (Galectin-3, Bcl-2, Bax, Survivin) im Rahmen der Progression der Malignität von Schilddrüsentumoren und deren klinische Bedeutung

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Summary

Background

Papillary carcinoma of the thyroid (PTC) is generally a slow growing tumor with favorable prognosis, while anaplastic thyroid carcinoma (ATC) is highly aggressive malignancy. Genetic defects in apoptotic pathways may contribute to differences in their biological behavior.

Methods

In this study, we analyzed immunohistochemically the expression of apoptosis-related molecules: galectin-3, Bcl-2, survivin (antiapoptotic), and Bax (pro-apoptotic), in archival tissue sections of PTC (n = 69) and ATC (n = 30) and correlated the results with clinicopathological parameters of these tumors.

Results

Galectin-3 and Bcl-2 showed a similar trend of down-regulation from high levels of both in PTC to low levels in ATC (p < 0.05). Bax was expressed at high levels in both type of thyroid carcinoma. Expression of survivin increased from PTC to ATC (p < 0.05), which may, at least in part, further facilitate the ability of malignant thyroid cell of ATC to escape programmed cell death despite high Bax expression. Only survivin, but not galectin-3, Bcl-2, or Bax, correlated significantly with lymph node metastasis presence and advanced stages of malignancy.

Conclusions

In conclusion, this study documented down-regulation of galectin-3 and Bcl-2 (antiapoptotic molecules) and stepwise increase of survivin (inhibitor of apoptosis), during thyroid tumor progression from PTC to ATC. Correlation of high survivin expression with aggressive behavior implies its role in progression of thyroid tumor malignancy and suggests that survivin could be a useful tool in the prediction of aggressiveness of a subset of papillary carcinomas and a possible target for molecular therapy for ATC patients.

Zusammenfassung

Grundlagen

Das papilläre Schilddrüsenkarzinom (PTC) ist im Allgemeinen ein langsam wachsender Tumor mit einer guten Prognose. Das anaplastische Schilddrüsenkarzinom (ATC) dahingegen ist ein hoch aggressiver bösartiger Tumor. Genetische Defekte der Apoptose könnten zu diesen Unterschieden im biologischen Verhalten beitragen.

Methodik

In dieser Studie analysierten wir in Gewebsschnitten aus dem Archivmaterial von 69 PTC und 30 ATC histochemisch die Expression von Molekülen, die mit der Apoptose einen Zusammenhang haben: Galectin-3, Bcl-2, Survivin (antiapoptotisch) und Bax (proapoptotisch). Die Ergebnisse wurden mit klinisch-pathologischen Parametern dieser Tumore korreliert.

Ergebnisse

Galectin-3 und Bcl-2 zeigten einen ähnlichen Trend der Down-Regulation von hohen Werten beim PTC zu niedrigen Werten beim ATC (p < 0,05). Bax wurde in beiden Karzinomtypen hoch exprimiert. Die Expression von Survivin stieg von PTC zum ATC an (p < 0,05). Dies könnte zumindest teilweise die Fähigkeit der malignen Schilddrüsenzelle des ATC zusätzlich erleichtern, dem programmierten Zelltod trotz hoher Bax Expression zu entkommen. Nur Survivin, nicht jedoch Galectin-3, Bcl-2 oder Bax, korrelierte signifikant mit dem Vorhandensein von Lymphknotenmetastasen und fortgeschrittenen Stadien der Bösartigkeit.

Schlussfolgerungen

Zusammenfassend dokumentierte unsere Studie eine Down-Regulation von Galektin3 und Bcl-2 (antiapoptotische Moleküle) und einen stufenweise Anstieg von Survivin (Hemmer der Apoptose) während der Progression der Malignität von Schilddrüsentumoren vom PTC zum ATC. Die Korrelation von hoher Survivin Expression mit dem aggressiven Verhalten des Tumors impliziert dessen Rolle bei der Progression der Bösartigkeit von Schilddrüsentumoren. Survivin könnte daher ein nützlicher Parameter zur Vorhersage der Aggressivität einer Untergruppe von PTC sein. Außerdem wäre es ein mögliches Ziel einer molekularen Therapie von Patienten mit ATC.

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References

  1. Van der Laan B, Freeman JL, Tsang RW, Asa SL. The association of well-differentiated thyroid carcinoma with insular or anaplastic thyroid carcinoma: Evidence for dedifferentiation in tumor progression. Endocr Pathol. 1993;4:215–21.

    Article  Google Scholar 

  2. Li Volsi VA. Surgical pathology of the thyroid. Philadelphia: WB Saunders; 1990. S. 136–72.

    Google Scholar 

  3. Mazzaferri EL, Jhiang S. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97:418–28.

    Article  CAS  PubMed  Google Scholar 

  4. Giuffrida D, Gharib H. Anaplastic thyroid carcinoma: current diagnosis and treatment. Ann Oncol. 2000;11:1083–9.

    Article  CAS  PubMed  Google Scholar 

  5. Wiseman SM, Masoudi H, Niblock P, Turbin D, Rajput A, Hay J, et al. Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment. Ann Surg Oncol. 2007;14:719–29.

    Article  PubMed  Google Scholar 

  6. Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. 2009;16:17–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Burlacu A. Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med. 2003;7:249–57.

    Article  CAS  PubMed  Google Scholar 

  8. Perillo NL, Marcus ME, Baum LG. Galectins: versatile modulators of cell adhesion, cell proliferation and cell death. J Mol Med. 1998;76:402–12.

    Article  CAS  PubMed  Google Scholar 

  9. Califice S, Castronovo V, Van Den Brule F. Galectin-3 and cancer (Review). Int J Oncol. 2004;25:983–92.

    CAS  PubMed  Google Scholar 

  10. Xu XC, El-Naggar AK, Lotan R. Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications. Am J Pathol. 1995;147:815–22.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Cvejic D, Savin S, Paunovic I, Tatic S, Havelka M, Sinadinovic J. Immunohistochemical localization of galectin-3 in malignant and benign human thyroid tissue. Anticancer Res. 1998;18:2637–42.

    CAS  PubMed  Google Scholar 

  12. Akahani S, Nangia-Makker P, Inohara H, Chol Kim H-R, Raz A. Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res. 1997;57:5272–6.

    CAS  PubMed  Google Scholar 

  13. Nakahara S, Oka N, Raz A. On the role of galectin-3 in cancer apoptosis. Apoptosis. 2005;10:267–75.

    Article  CAS  PubMed  Google Scholar 

  14. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3:917–21.

    Article  CAS  PubMed  Google Scholar 

  15. Deveraux QL, Reed JC. IAP family proteins—suppressors of apoptosis. Genes Dev. 1999;13:239–52.

    Article  CAS  PubMed  Google Scholar 

  16. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14:5000–5.

    Article  CAS  PubMed  Google Scholar 

  17. Waligórska-Stachura J, Jankowska A, Was´ko R, Liebert W, Biczysko M, Czarnywojtek A, et al. Survivin-prognostic tumor biomarker in human neoplasms-review. Ginekol Pol. 2012;83:537–40.

    PubMed  Google Scholar 

  18. Ito Y, Yoshida H, Uruno T, Nakano K, Miya A, Kobayashi K, et al. Survivin expression is significantly linked to the dedifferentiation of thyroid carcinoma. Oncol Rep. 2003;10:1337–40.

    PubMed  Google Scholar 

  19. Antonaci A, Consorti F, Mardente S, Natalizi S, Giovannone G, Della Rocca C. Survivin and cyclin D1 are jointly expressed in thyroid papillary carcinoma and microcarcinoma. Oncol Rep. 2008;20:63–7.

    PubMed  Google Scholar 

  20. Chen Z, Liu N, Zhu G, Dralle H, Hoang-Vu C. Targeting of the anti-apoptotic gene survivin in human thyroid carcinoma. Int J Mol Med. 2012;30:465–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Pannone G, Santoro A, Pasquali D, Zamparese R, Mattoni M, Russo G, et al. The role of survivin in thyroid tumors: differences of expression in well-differentiated, non-well-differentiated, and anaplastic thyroid cancers. Thyroid. 2014;24:511–9.

    Article  CAS  PubMed  Google Scholar 

  22. Sobin LH, Wittekind Ch, editors. International Union Against Cancer (UICC). TNM classification of malignant tumors. 6th ed. New York: Wiley-Liss; 2002.

  23. Lin CI, Wang EE, Abramson MA, Donner DB, Bertagnolli MM, Moore FD Jr., Ruan DT. Galectin-3 regulates apoptosis and doxorubicin chemoresistance in papillary thyroid cancer cells. Biochem Biophys Res Commun. 2009;379:626–31.

    Article  CAS  PubMed  Google Scholar 

  24. Yang R-Y, Hsu DK, Liu F-T. Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci USA. 1996;93:6737–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Pollina L, Pacini F, Fontanini G, Vignati S, Bevilacqua G, Basolo F. Bcl-2, p53 and proliferating cell nuclear antigen expression are related to the degree of differentiation in thyroid carcinomas. Br J Cancer. 1996;73:139–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Tirrò E, Consoli ML, Massimino ML, Manzella L, Frasca F, Sciacca L, et al. Altered expression of c-IAP1, survivin, and Smac contributes to chemotherapy resistance in thyroid cancer cells. Cancer Res. 2006;66:4263–72.

    Article  PubMed  Google Scholar 

  27. Orlandi F, Saggiorato E, Pivano G, Puligheddu B, Termine A, Cappia S, et al. Galectin-3 is a presurgical marker of human thyroid carcinoma. Cancer Res. 1998;58:3013–20.

    Google Scholar 

  28. Cvejic DS, Savin SB, Petrovic IM, Paunovic IR, Tatic SB, Havelka MJ. Galectin-3 expression in papillary thyroid carcinoma: relation to histomorphologic growth pattern, lymph node metastasis, extrathyroid invasion, and tumor size. Head Neck. 2005;12:1049–55.

    Article  Google Scholar 

  29. Türköz HK, Oksüz H, Yurdakul Z, Ozcan D. Galectin-3 expression in tumor progression and metastasis of papillary thyroid carcinoma. Endocr Pathol. 2008;19:92–6.

    Article  PubMed  Google Scholar 

  30. Kawachi K, Yoshifumi M, Yonezawa S, Nakano S, Shirao K, Natsugoe S, et al. Galectin-3 expression in various thyroid neoplasms and its possible role in metastasis formation. Hum Pathol. 2000;31:428–33.

    Article  CAS  PubMed  Google Scholar 

  31. Aksoy M, Giles Y, Kapran Y, Terzioglu T, Tezelman S. Expression of Bcl-2 in papillary thyroid cancers an its prognostic value. Acta Chir Belg. 2005;105:644–8.

    CAS  PubMed  Google Scholar 

  32. Martinez-Brocca MA, Castilla C, Navarro E, Amaya MJ, Travado P, Japon MA, Saez C. Clinicopathological correlation of Bcl-xL and Bax expression in differentiated thyroid carcinoma. Clin Endocrinol (Oxf). 2008;68:190–7.

    CAS  Google Scholar 

  33. Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T, Altieri DC. IAP regulation of metastasis. Cancer Cell. 2010;17:53–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgment

The authors are grateful to Dr J. Anna Nikolic, for language correction of the manuscript. This work is supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, project 173050: “Molecular characterization of thyroid gland tumors: biological and clinical aspects”.

Conflict of interest

No actual or potential conflicts of interest exist.

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Authors and Affiliations

  1. Institute for the Application of Nuclear Energy—INEP, University of Belgrade, Banatska 31b, 11080, Zemun—Belgrade, Serbia

    Sonja A. Selemetjev MSc, Svetlana B. Savin &  Dubravka Cvejic

  2. Center for Endocrine Surgery, Institute for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, Belgrade, Serbia

    Ivan R. Paunovic

  3. Institute of Pathology, Medical Faculty, University of Belgrade, Belgrade, Serbia

    Svetislav B. Tatic

Authors
  1. Sonja A. Selemetjev MSc
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  2. Svetlana B. Savin
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  5. Dubravka Cvejic
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Correspondence to Dubravka Cvejic.

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Selemetjev, S., Savin, S., Paunovic, I. et al. Changes in the expression pattern of apoptotic molecules (galectin-3, Bcl-2, Bax, survivin) during progression of thyroid malignancy and their clinical significance. Wien Klin Wochenschr 127, 337–344 (2015). https://doi.org/10.1007/s00508-014-0674-6

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