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Methylation levels of sodium–iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression

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Abstract

DNA methylation regulates gene expression. Aberrant methylation plays an important role in human tumorigenesis. We have previously detected reduced NIS mRNA expression in thyroid tumors as compared to non-tumor tissues. Thus, in this study we investigated whether the methylation of the CpG-island located in the NIS gene promoter was associated with reduced mRNA expression in thyroid tumors. Methylation levels of 30 pairs of samples from 10 benign and 20 malignant thyroid tumors (T) along with matched non-tumor (NT) areas were determined by semiquantitative methylation specific-PCR. NIS methylation was detected in all samples. Methylation levels and frequencies did not differ between the groups and were not associated with BRAF mutational status. Highest methylation levels and frequencies were detected in the 5′ region of the CpG-island decreasing toward the 3′ end. Intraindividual analysis (T versus NT) showed high tumor methylation levels in 40 % of the samples in the benign group and 30 % in the malignant group, associated with low NIS mRNA expression. No quantitative correlation was detected between methylation levels and mRNA expression in any the groups. The results of this study showed that methylation of NIS promoter is a very frequent event in both benign and malignant tumors as well as in their surrounding tissues, and characterized a non-homogeneous methylation pattern along the CpG island. Therefore, further investigations involving other sites that may be implicated in methylation regulation of NIS expression are warranted.

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References

  1. N. Carrasco, Iodide transport in the thyroid gland. Biochim. Biophys. Acta 1154(1), 65–82 (1993)

    Article  PubMed  CAS  Google Scholar 

  2. O. Dohan, A. De la Vieja, V. Paroder, C. Riedel, M. Artani, M. Reed et al., The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr. Rev. 24(1), 48–77 (2003)

    Article  PubMed  CAS  Google Scholar 

  3. M. Rodriguez-Paredes, M. Esteller, Cancer epigenetics reaches mainstream oncology (Review). Nat. Med. 17(3), 330–339 (2011)

    Article  PubMed  CAS  Google Scholar 

  4. Xing M. Gene methylation in thyroid tumorigenesis. Endocrinology. 148(3), 948–953 (2007) (Research Support, Non-U.S. Gov’t Review)

    Google Scholar 

  5. A.K. Sodre, I.G. Rubio, A.L. Galrao, M. Knobel, E.K. Tomimori, V.A. Alves et al., Association of low sodium–iodide symporter messenger ribonucleic acid expression in malignant thyroid nodules with increased intracellular protein staining. J. Clin. Endocrinol. Metab. 93(10), 4141–4145 (2008)

    Article  PubMed  CAS  Google Scholar 

  6. S. Trouttet-Masson, S. Selmi-Ruby, F. Bernier-Valentin, V. Porra, N. Berger-Dutrieux, M. Decaussin et al., Evidence for transcriptional and posttranscriptional alterations of the sodium/iodide symporter expression in hypofunctioning benign and malignant thyroid tumors. Am. J. Pathol. 165(1), 25–34 (2004)

    Article  PubMed  CAS  Google Scholar 

  7. G.M. Venkataraman, M. Yatin, R. Marcinek, K.B. Ain, Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I-symporter gene methylation status. J. Clin. Endocrinol. Metab. 84(7), 2449–2457 (1999)

    Article  PubMed  CAS  Google Scholar 

  8. S. Neumann, K. Schuchardt, A. Reske, P. Emmrich, R. Paschke, Lack of correlation for sodium iodide symporter mRNA and protein expression and analysis of sodium iodide symporter promoter methylation in benign cold thyroid nodules. Thyroid 14(2), 99–111 (2004)

    Article  PubMed  CAS  Google Scholar 

  9. J.K. Stephen, D. Chitale, V. Narra, K.M. Chen, R. Sawhney, M.J. Worsham, DNA methylation in thyroid tumorigenesis. Cancers (Basel) 3(2), 1732–1743 (2011)

    CAS  Google Scholar 

  10. J.A. Smith, C.Y. Fan, C. Zou, D. Bodenner, M.S. Kokoska, Methylation status of genes in papillary thyroid carcinoma. Arch. Otolaryngol. Head Neck Surg. 133(10), 1006–1011 (2007)

    Article  PubMed  Google Scholar 

  11. K. Woodson, R. Hayes, L. Wideroff, L. Villaruz, J. Tangrea, Hypermethylation of GSTP1, CD44, and E-cadherin genes in prostate cancer among US Blacks and Whites. Prostate 55(3), 199–205 (2003)

    Article  PubMed  CAS  Google Scholar 

  12. G. Oler, J.M. Cerutti, High prevalence of BRAF mutation in a Brazilian cohort of patients with sporadic papillary thyroid carcinomas: correlation with more aggressive phenotype and decreased expression of iodide-metabolizing genes. Cancer 115(5), 972–980 (2009)

    Article  PubMed  CAS  Google Scholar 

  13. G. Riesco-Eizaguirre, I. Rodriguez, A. De la Vieja, E. Costamagna, N. Carrasco, M. Nistal et al., The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. 69(21), 8317–8325 (2009)

    Article  PubMed  CAS  Google Scholar 

  14. P.A. Jones, Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13(7), 484–492 (2012)

    Article  PubMed  CAS  Google Scholar 

  15. M.J. Provenzano, M.P. Fitzgerald, K. Krager, F.E. Domann, Increased iodine uptake in thyroid carcinoma after treatment with sodium butyrate and decitabine (5-Aza-dC). Otolaryngol. Head Neck Surg. 137(5), 722–728 (2007)

    Article  PubMed  Google Scholar 

  16. Russo D, Damante G, Puxeddu E, Durante C, Filetti S. Epigenetics of thyroid cancer and novel therapeutic targets. J Mol Endocrinol. 46(3), R73–81 (2011) (Research Support, Non-U.S. Gov’t Review)

    Google Scholar 

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Acknowledgments

This study was supported by Grants: 2007/51235-7, 2007/51236-3 and 2009/52517-1 from the Fundacão de Amparo a Pesquisa do Estado de São Paulo (FAPESP), São Paulo, Brazil, and a partial financial Grant from the Instituto da Tiroide, São Paulo, Brazil.

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The authors have nothing to disclose.

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Authors and Affiliations

  1. Thyroid Unit, Cellular and Molecular Endocrine Laboratory, LIM-25, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

    A. L. Galrão, A. K. Sodré, R. Y. Camargo, E. U. Lima & G. Medeiros-Neto

  2. Head and Neck Surgery of Santa Catarina Hospital, São Paulo, Brazil

    C. U. Friguglietti

  3. Head and Neck Surgery of Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil

    M. A. Kulcsar

  4. Department of Biological Sciences, Federal University of São Paulo (UNIFESP), Rua Prof. Artur Riedel 275, Eldorado, Diadema, SP, 09972-270, Brazil

    I. G. S. Rubio

Authors
  1. A. L. Galrão
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  2. A. K. Sodré
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  3. R. Y. Camargo
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  4. C. U. Friguglietti
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  5. M. A. Kulcsar
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  6. E. U. Lima
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  7. G. Medeiros-Neto
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  8. I. G. S. Rubio
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Correspondence to I. G. S. Rubio.

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Galrão, A.L., Sodré, A.K., Camargo, R.Y. et al. Methylation levels of sodium–iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression. Endocrine 43, 225–229 (2013). https://doi.org/10.1007/s12020-012-9779-8

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  • DOI: https://doi.org/10.1007/s12020-012-9779-8

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