Sodium Iodide Symporter in Thyroid Carcinoma

  • June-Key Chung
Part of the Medical Radiology book series (MEDRAD)


Thyroid iodide uptake is essential for the clinical application of radioiodine in patients with well-differentiated thyroid carcinoma. Iodide uptake occurs across the plasma membranes of thyroid follicular cells and cancer cells via an active transporter process mediated by sodium iodide symporter (NIS). The cloning of the NIS gene enabled the molecular mechanisms underlying iodide transport to be better characterized, and thus, opened the way to the expansion of its role in thyroid carcinoma. Thyroid-stimulating hormone (TSH) is the principal regulator of iodide uptake, although many other factors, including insulin, insulin-like growth factor I, epidermal growth factor, and iodide itself, also influence iodide uptake by the thyroid gland. Human NIS expression may be increased, decreased, or absent in well-differentiated thyroid cancer. However, the reason for reduced iodide uptake in well-differentiated thyroid carcinoma is not solely due to lower NIS expression, and probably depends on a complex combination of regulatory changes that ultimately affect NIS expression, targeting, or activation. Nevertheless, reduced functional levels of NIS on cell membranes do account for the reduced iodide uptake observed in thyroid carcinoma. Furthermore, thyroid cancer tissues expressing NIS take up more I-131 than those not expressing NIS, and these tumors subsequently show a higher rate of response to radioiodine therapy. Accordingly, NIS appears to have the potential to expand the role of nuclear medicine in the management of thyroid carcinoma.


Thyroid Cancer Thyroid Cancer Cell Radioiodine Uptake Iodide Uptake Iodide Transport 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ajjan RA, Watson FF, Findlay C et al (1998a) The sodium iodide symporter gene and its regulation by cytokines found in autoimmunity. J Endocrinol 158:351–358PubMedCrossRefGoogle Scholar
  2. Ajjan RA, Kamaruddin NA, Crisp M, Watson PF, Ludgate M, Weetman AP (1998b) Regulation and tissue distribution of the human sodium iodide symporter gene. Clin Endocrinol 49:517–523CrossRefGoogle Scholar
  3. Arturi F, Russo D, Schlumberger M et al (1998) Iodide symporter gene expression in human thyroid tumors. J Clin Endocrinol Metab 83:2493–2496PubMedGoogle Scholar
  4. Baumann E (1986) Uber den Jodgehalt der Schilddrusen von Mechen und tieren. Hoppe-Seyler’s Zeitsehrift fur Physiologische Chemie 22:1–17Google Scholar
  5. Caillou B, Troalen F, Baudin E et al (1998) Na+/I-symporter distribution in human thyroid tissues: an immunohistochemical study. J Clin Endocrinol Metab 83:4102–4106PubMedGoogle Scholar
  6. Chung J-K (2002) Sodium/iodide symporter: its role in nuclear medicine. J Nucl Med 43:1188–1200PubMedGoogle Scholar
  7. Chung J-K, So Y, Lee JS et al (1999) Value of FDG PET in papillary thyroid carcinoma with negative 131I whole-body scan. J Nucl Med 40:986–992PubMedGoogle Scholar
  8. Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter. Nature 379:458–460PubMedCrossRefGoogle Scholar
  9. Dohan O, Baloch Z, Banrevi Z, Livolsi V, Carrasco N (2001) Predominant intracellular overexpression of the Na+/I-symporter (NIS) in a large sampling of thyroid cancer cases. J Clin Endocrinol Metab 86:2697–2700PubMedGoogle Scholar
  10. Dohan O, Ginter CS, Carrasco N (2005) Role of the NIS (Na+/I-symporter) carboxy terminus in iodide transport. Thyroid 15:S48Google Scholar
  11. Endo T, Kaneshige M, Nakazato M et al (1997) Thyroid transcription factor-1 activates the promoter rat Na+/I-symporter gene. Mol Endocrinol 11:1747–11755PubMedGoogle Scholar
  12. Eng PH, Cardona GR, Fang SL et al (1999) Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 140:3401–3410Google Scholar
  13. Eskandari S, Loo DDF, Dai G, Levy O, Wright EM, Carrasco N (1997) Thyroid Na+/I-symporter. J Biol Chem 272:27230–27238PubMedCrossRefGoogle Scholar
  14. Filetti S, Bidart J-M, Arturi F, Caillou B, Russo D, Schlumberger M (1999) Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism. Eur J Endocrinol 141:443–457PubMedCrossRefGoogle Scholar
  15. Fugazzola L, Puxeddu E, Avenia N et al (2006) Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr Relat Cancer 13:455–464PubMedCrossRefGoogle Scholar
  16. Furlanetto TW, Nguyen LO, Jameson JL (1999) Estradiol increases proliferation and down-regulates the sodium/iodide symporter gene in FRTL-5cells. Endocrinology 140:5705–5711PubMedGoogle Scholar
  17. Jung YH, Hah JH, Sung M-W et al (2009) Reciprocal immunohistochemical expression of sodium/iodide symporter and hexokinase I in primary thyroid tumors with synchronous cervical metastasis. Laryngoscope 119:541–548PubMedCrossRefGoogle Scholar
  18. Kogai T, Endo T, Saito T et al (2000a) Induction of follicular formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. J Endocrinol 167:125–135PubMedCrossRefGoogle Scholar
  19. Kogai T, Schultz JJ, Johnson LS, Huang M, Brent GA (2000b) Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line. Proc Natl Acad Sci U S A 97:8519–8524PubMedCentralPubMedCrossRefGoogle Scholar
  20. Kogai T, Hershman JM, Motomura K, Endo T, Onaya T, Brent GA (2001) Differential regulation of the human sodium/iodide symporter gene promoter in papillary thyroid carcinoma cell lines and normal thyroid cells. Endocrinology 142:3369–3379PubMedCrossRefGoogle Scholar
  21. Kogai T, Taki K, Brent GA (2006) Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer 13:797–826PubMedCrossRefGoogle Scholar
  22. Lazar V, Bidart J-M, Caillou B et al (1999) Expression of the Na/I symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab 84:3228–3234PubMedGoogle Scholar
  23. Lee BW, Lee DS Moon DH et al (1990) Comparison of I-131 diagnostic scan and therapeutic scan in thyroid carcinoma. Nucl Med Mol Imaging 24:80–86Google Scholar
  24. Levy O, De la Vieja A, Carrasco N (1998) The Na+/I-symporter (NIS): recent advances. J Bioenerg Biomembr 30:195–206PubMedCrossRefGoogle Scholar
  25. Magliano MP, Lauro RD, Zannini M (2000) Pax8 has a key role in thyroid cell differentiation. Proc Natl Acad Sci U S A 97:13144–13149CrossRefGoogle Scholar
  26. Min J-J, Chung J-K, Lee YJ et al (2001) Relationship between expression of the sodium/iodide symporter and I-131 uptake in recurrent lesions of differentiated thyroid carcinoma. Eur J Nucl Med 28:639–645CrossRefGoogle Scholar
  27. Ohmori M, Endo T, Harii N, Onaya T (1998) A novel thyroid transcription factor is essential for thyrotropin-induced up-regulation of Na+/I-symporter gene expression. Mol Endocrinol 12:727–736PubMedGoogle Scholar
  28. Park HJ, Kim JY, Park KY, Gong G, Hong SJ, Ahn IM (2000) Expressions of human sodium iodide symporter mRNA in primary and metastatic papillary thyroid carcinoma. Thyroid 10:211–217PubMedCrossRefGoogle Scholar
  29. Pekari AE, Hersam JM (1998) Tumor necrosis factor, ceremide, transforming growth factor-beta1 and aging reduce Na+/I-symporter messenger ribonucleic acid levels in FRTL-5 cells. Endocirnology 139:7033712Google Scholar
  30. Riedel C, Levy O, Carrasco N (2001) Post-transcriptional regulation of sodium/iodide symporter by thyrotropin. J Biol Chem 276:21458–21463PubMedCrossRefGoogle Scholar
  31. Riesco-Eizaguirre G, Santisteban P (2006) A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol 155:495–512PubMedCrossRefGoogle Scholar
  32. Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia’-Cabezas M, Nistal M, Santisteban P (2006) The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na/I targeting to the membrane. Endocr Relat Cancer 13:257–269Google Scholar
  33. Riggs DS (1952) Quantitative aspects of iodine metabolism in man. Pharmacol Rev 4:284–370PubMedGoogle Scholar
  34. Saito T, Endo T, Kawaguchi A et al (1998) Increased expression of the sodium/iodide symporter in papillary thyroid carcinomas. J Clin Invest 101:1296–1300PubMedCentralPubMedCrossRefGoogle Scholar
  35. Shen DHY, Kloos RT, Mazaferri EL, Jhiang SM (2001) Sodium iodide symporter in health and disease. Thyroid 11:415–425PubMedCrossRefGoogle Scholar
  36. Smanik PA, Liu Q, Furminger TL et al (1996) Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 226:339–345PubMedCrossRefGoogle Scholar
  37. Spitzweg C, Heufelder AE (1998) The sodium iodide symporter: its emerging relevance to clinical thyroidology. Eur J Endocrinol 138:374–375PubMedCrossRefGoogle Scholar
  38. Spitzweg C, Joba W, Eisenmenger W, Heufelder AE (1998) Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland, mammary gland, and gastric mucosa. J Clin Endocrinol Metab 83:1746–1751PubMedCrossRefGoogle Scholar
  39. Tazebay UH, Wapnir IL, Levy O et al (2000) The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med 6:871–878PubMedCrossRefGoogle Scholar
  40. Trapasso F, Iuliano R, Chiefari E et al (1999) Iodide symporter gene expression in normal and transformed rat thyroid cells. Eur J Endocrinol 140:447–451PubMedCrossRefGoogle Scholar
  41. Trouttet-Masson S, Selmi-Ruby S, Bernier-Valentin F et al (2004) Evidence for transcriptional and posttranscriptional alterations of the sodium/iodide symporter expression in hypofunctioning benign and malignant thyroid tumors. Am J Pathol 165:25–34PubMedCentralPubMedCrossRefGoogle Scholar
  42. Trovisco V, Vieira de Castro I, Soares P et al (2004) BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol 202:247–251Google Scholar
  43. Uyttersprot N, Pelgrims N, Carrasco N et al (1997) Moderate doses of iodide in vivo inhibit cell proliferation and expression of thyroid peroxidase and the Na+/I-symporter mRNAs in dog thyroid. Mol Cell Endocrinol 131:195–203PubMedCrossRefGoogle Scholar
  44. Vadyssirisack DD, Chen E, Zhang Z et al (2007) Identification of in vivo phosphorylation sites and their functional significance in the sodium iodide symporter. J Biol Chem 282:36820–36828CrossRefGoogle Scholar
  45. Wapnir IL, van de Rijn M, Nowels K et al (2003) Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast and other carcinomas using high density tissue microarrays and conventional sections. J Clin Endocrinol Metab 88:1880–1888PubMedCrossRefGoogle Scholar
  46. Weiss SJ, Philip NJ, Ambesi-Impiombato FS, Grollman EF (1984) Thyrotropin-stimulated iodide transport mediated by adenosine 3′,5′-monophosphate and dependent on protein synthesis. Endocrinology 114:1099–1107PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Nuclear MedicineCancer Research Institute, Seoul National University College of MedicineSeoulKorea

Personalised recommendations