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The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults

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Tumor Biology

Abstract

Ezrin is a protein that functions as a cross-linker between actin cytoskeleton and plasma membrane. Its clinical role in osteosarcoma is unclear. The aim of this study was to investigate, in osteosarcoma, the prognostic value of ezrin expression at biopsy and changes in expression levels after preoperative chemotherapy. Thirty-eight newly diagnosed osteosarcoma patients aged 6–23 years were included. At diagnosis, 20 patients had localized disease, the others had distant metastases. Median follow-up was 75 months (range 13–135). Ezrin expression was assessed immunohistochemically in biopsy tissue and primary tumour specimens resected after chemotherapy. The influence on survival of changes in ezrin expression after chemotherapy was analysed. Ezrin expression was significantly higher after preoperative chemotherapy and changes compared to biopsy tissue were significantly lower in patients with early progression than in patients with relapse or no further evidence of disease (p = 0.006 and p = 0.002, respectively). Similarly, ezrin expression was higher after preoperative chemotherapy and exhibited less change in expression in deceased patients compared to patients surviving more than 5 years (both p = 0.001). Ezrin expression at biopsy was significantly associated with both histopathological aggressiveness (p < 0.001) and tumour size (p = 0.037). The results of this study provide evidence that changes in overexpression of ezrin due to preoperative chemotherapy could be a useful predictive and prognostic marker in patients with osteosarcoma.

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References

  1. Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, Dimitrova N, Jakab Z, Kaatsch P, Lacour B, Mallone S, Marcos-Gragera R, Minicozzi P, Sánchez-Pérez MJ, Sant M, Santaquilani M, Stiller C, Tavilla A, Trama A, Visser O, Peris-Bonet R, the EUROCARE Working Group. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5-a population-based study. Lancet Oncol. 2014;15:35–47.

    Article  PubMed  Google Scholar 

  2. Jaffe N. Historical perspective on the introduction and use of chemotherapy for the treatment of osteosarcoma. Adv Exp Med Biol. 2014;804:1–30.

    Article  CAS  PubMed  Google Scholar 

  3. Bakhshi S, Radhakrishnan V. Prognostic markers in osteosarcoma. Expert Rev Anticancer Ther. 2010;10:271–87.

    Article  PubMed  Google Scholar 

  4. Meyers P. Prognostic factors for sarcomas: hard and soft. J Clin Oncol. 2002;20:627–9.

    PubMed  Google Scholar 

  5. Bianchi E, Artico M, Di Cristofano C, Leopizzi M, Taurone S, Pucci M, Gobbi P, Mignini F, Petrozza V, Pindinello I, Conconi MT, Della RC. Growth factors, their receptor expression and markers for proliferation of endothelial and neoplastic cells in human osteosarcoma. Int J Immunopathol Pharmacol. 2013;26:621–32.

    CAS  PubMed  Google Scholar 

  6. Yang J, Zhang W. New molecular insights into osteosarcoma targeted therapy. Curr Opin Oncol. 2013;25:398–406.

    Article  CAS  PubMed  Google Scholar 

  7. Ługowska I, Woźniak W, Klepacka T, Michalak E, Szamotulska K. A prognostic evaluation of vascular endothelial growth factor in children and young adults with osteosarcoma. Pediatr Blood Cancer. 2011;57:63–8.

    Article  PubMed  Google Scholar 

  8. Hunter KW. Ezrin, a key component in tumour metastasis. Trends Mol Med. 2004;10:201–4.

    Article  CAS  PubMed  Google Scholar 

  9. Bulut G, Hong SH, Chen K, Beauchamp EM, Rahim S, Kosturko GW, Glasgow E, Dakshanamurthy S, Lee HS, Daar I, Toretsky JA, Khannaand C, Üren A. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene. 2012;31:269–81.

    Article  CAS  PubMed  Google Scholar 

  10. Singh V, Lin R, Yang J, Cha B, Sarker R, Tse CM, Donowitz M. AKT and GSK-3 are necessary for direct ezrin binding to NHE3 as part of a C-terminal stimulatory complex: role of a novel Ser-rich NHE3 C-terminal motif in NHE3 activity and trafficking. J Biol Chem. 2014;289:5449–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ardura JA, Wang B, Watkins SC, Vilardaga JP, Friedman PA. Dynamic Na+-H+ exchanger regulatory factor-1 association and dissociation regulate parathyroid hormone receptor trafficking at membrane microdomains. J Biol Chem. 2011;286:35020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chiappetta C, Leopizzi M, Censi F, Puggioni C, Petrozza V, Carlo R, Di Cristofano C. Correlation of the Rac1/RhoA pathway with ezrin expression in osteosarcoma. Appl Immunohistochem Mol Morphol. 2014;22:162–70.

    Article  CAS  PubMed  Google Scholar 

  13. Briggs JW, Ren L, Nguyen R, Chakrabarti K, Cassavaugh J, Rahim S, Bulut G, Zhou M, Veenstra TD, Chen Q, Wei JS, Khan J, Uren A, Khanna C. The ezrin metastatic phenotype is associated with the initiation of protein translation. Neoplasia. 2012;14:297–310.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Köbel M, Gradhand E, Zeng K, Schmitt W, Kriese K, Lantzsch T, Wolters M, Dittmer J, Strauss HGMD, Thomssen C, Hauptmann S. Ezrin promotes ovarian carcinoma cell invasion and its retained expression predicts poor prognosis in ovarian carcinoma. Int J Gynecol Pathol. 2006;25:121–30.

    Article  PubMed  Google Scholar 

  15. Carneiro A, Bendahl PO, Åkerman M, Domanski HA, Rydholm A, Engellau J, Nilbert M. Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas. J Clin Pathol. 2011;64:689–94.

    Article  PubMed  Google Scholar 

  16. Ma L, Liu YP, Zhang XH, Geng CZ, Li ZH. Relationship of RhoA signaling activity with ezrin expression and its significance in the prognosis for breast cancer patients. Chin Med J. 2013;126:242–7.

    CAS  PubMed  Google Scholar 

  17. Zhu L, Ito T, Nakahara T, Nagae K, Fuyuno Y, Nakao M, Akahoshi M, Nakagawa R, Tu Y, Uchi H, Furue M. Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma. J Dermatol. 2013;40:973–9.

    Article  CAS  PubMed  Google Scholar 

  18. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman LJ. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10:182–6.

    Article  CAS  PubMed  Google Scholar 

  19. Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S, Bottos A, Gammaitoni L, Migliardi G, Camussi G, Alberghini M, Torchio B, Ferrari S, Bussolino F, Fagioli F, Picci P, Aglietta M. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer. 2009;8:118.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Paige M, Kosturko G, Bulut G, Miessau M, Rahim S, Toretsky JA, Brown ML, Üren A. Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma. Bioorg Med Chem. 2014;22:478–87.

    Article  CAS  PubMed  Google Scholar 

  21. Park HR, Jung WW, Bacchini P, Bertoni F, Kim YW, Park YK. Ezrin in osteosarcoma: comparison between conventional high-grade and central low-grade osteosarcoma. Pathol Res Pract. 2006;202:509–15.

    Article  CAS  PubMed  Google Scholar 

  22. Wang YF, Shen JN, Xie XB, Wang J, Huang G. Expression change of ezrin as a prognostic factor in primary osteosarcoma. Med Oncol. 2011;28:636–43.

    Article  CAS  Google Scholar 

  23. Khanna C, Khan J, Nguyen P, Prehn J, Caylor J, Yeung C, Trepel J, Meltzer P, Helman L. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res. 2001;61:3750–9.

    CAS  PubMed  Google Scholar 

  24. Leonard P, Sharp T, Henderson S, Hewitt D, Pringle J, Sandison A, Goodship A, Whelan J, Boshoff C. Gene expression array profile of human osteosarcoma. Br J Cancer. 2003;89:2284–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mu Y, Zhang H, Che L, Li K. Clinical significance of microRNA-183/ezrin axis in judging the prognosis of patients with osteosarcoma. Med Oncol. 2014;31:1–7.

    Article  Google Scholar 

  26. Salas S, de Pinieux G, Gomez-Brouchet A, Larrousserie F, Leroy X, Aubert S, Decouvelaere AV, Giorgi R, Fernandez C, Bouvieret C. Ezrin immunohistochemical expression in cartilaginous tumours: a useful tool for differential diagnosis between chondroblastic osteosarcoma and chondrosarcoma. Virchows Arch. 2009;454:81–7.

    Article  CAS  PubMed  Google Scholar 

  27. Xu-Dong S, Zan S, Shui-er Z, Li-na T, Wen-xi Y, Feng L, Yang Y. Expression of ezrin correlates with lung metastasis in Chinese patients with osteosarcoma. Clin Invest Med. 2009;32:180–8.

    Google Scholar 

  28. Ferrari S, Zanella L, Alberghini M, Palmerini E, Staals E, Bacchini P. Prognostic significance of immunohistochemical expression of ezrin in non-metastatic high-grade osteosarcoma. Pediatr Blood Cancer. 2008;50:752–6.

    Article  PubMed  Google Scholar 

  29. Salas S, Bartoli C, Deville JL, Gaudart J, Fina F, Calisti A, Bollini G, Curvale G, Gentet JC, Duffaud F, Figarella-Branger D, Bouvier C. Ezrin and alpha-smooth muscle actin are immunohistochemical prognostic markers in conventional osteosarcomas. Virchows Arch. 2007;451:999–1007.

    Article  CAS  PubMed  Google Scholar 

  30. Kim MS, Song WS, Cho WH, Lee SY, Jeon DG. Ezrin expression predicts survival in stage IIB osteosarcomas. Clin Orthop Relat Res. 2007;459:229–36.

    Article  PubMed  Google Scholar 

  31. Le Guellec S, Moyal ECJ, Filleron T, Delisle MB, Chevreau C, Rubie H, Castex MP, Sales de Gauzy J, Bonnevialle P, Gomez-Brouchet A. The β5/focal adhesion kinase/glycogen synthase kinase 3β integrin pathway in high-grade osteosarcoma: a protein expression profile predictive of response to neoadjuvant chemotherapy. Hum Pathol. 2013;44:2149–58.

    Article  PubMed  Google Scholar 

  32. Wang Z, He ML, Zhao JM, Qing HH, Wu Y. Meta-analysis of associations of the ezrin gene with human osteosarcoma response to chemotherapy and prognosis. Asian Pac J Cancer Prev. 2013;14:2753–8.

    Article  PubMed  Google Scholar 

  33. Lun DX, Hu YC, Xu ZW, Xu LN, Wang BW. The prognostic value of elevated ezrin in patients with osteosarcoma. Tumour Biol. 2014;35:1263–6.

    Article  CAS  PubMed  Google Scholar 

  34. Park HR, Cabrini RL, Araujo ES, Paparella ML, Brandizzi D, Park YK. Expression of ezrin and metastatic tumour antigen in osteosarcomas of the jaw. Tumori. 2009;95:81.

    CAS  PubMed  Google Scholar 

  35. Boldrini E, Peres SV, Morini S, de Camargo B. Immunoexpression of ezrin and CD44 in patients with osteosarcoma. J Pediatr Hematol Oncol. 2010;32:E213–7.

    Article  CAS  PubMed  Google Scholar 

  36. Ren L, Khanna C. Role of ezrin in osteosarcoma metastasis. In: Kleinerman ES, editor. Current advances in osteosarcoma. Springer International Publishing; 2014. pp. 181–201.

  37. Shang X, Wang Y, Zhao Q, Wu K, Li X, Ji X, He R, Zhang W. siRNAs target sites selection of ezrin and the influence of RNA interference on ezrin expression and biological characters of osteosarcoma cells. Mol Cell Biochem. 2012;364:363–71.

    Article  CAS  PubMed  Google Scholar 

  38. Wang Y, Shen J, Shang X, Wang J, Li J, Yin J, Zou C. Ezrin mRNA target site selection for DNAzymes using secondary structure and hybridization thermodynamics. Tumour Biol. 2011;324:809–17.

    Article  Google Scholar 

  39. Abdou AG, Kandil M, Asaad NY, Dawoud MM, Shahin AA, Abd Eldayem AF. The prognostic role of ezrin and HER2/neu expression in osteosarcoma. Appl Immunohistochem Mol Morphol. 2016;24(5):355–63.

  40. Li J, Wei K, Yu H, Jin D, Wang G, Yu B. Prognostic value of ezrin in various cancers: a systematic review and updated meta-analysis. Sci Rep. 2015;5:17903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

The study was financially supported by the research grant of National Science Centre (grant number: N N407 144838).

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, Institute of Mother and Child, M. Kasprzak Street 17a, 01-211, Warsaw, Poland

    Iwona Lugowska, Ewa Mierzejewska & Katarzyna Szamotulska

  2. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, K. W. Roentgen Street, 02-781, Warsaw, Poland

    Iwona Lugowska

  3. Department of Pathology, Institute of Mother and Child, M. Kasprzak Street 17a, 01-211, Warsaw, Poland

    Malgorzata Lenarcik, Teresa Klepacka, Irena Koch & Elzbieta Michalak

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  1. Iwona Lugowska
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Correspondence to Iwona Lugowska.

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The study was funded by the research grant of National Science Centre: grant number: N N407 144838.

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Lugowska, I., Mierzejewska, E., Lenarcik, M. et al. The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults. Tumor Biol. 37, 12071–12078 (2016). https://doi.org/10.1007/s13277-016-5091-1

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  • DOI: https://doi.org/10.1007/s13277-016-5091-1

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