Relation Between Iodide Transporters and Thyroid Diseases_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Heng , ZHU Jingqiang , LI Zhihui

Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

Keywords：

Thyroid disease; Na+/I- symporter; Pendrin; Human apical iodide transporter

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Objective 　To investigate the clinical significance of the three iodide transporters in thyroid diseases.
Methods 　Literatures about the Na+/I- symporter (NIS), pendrin and human apical iodide transporter (hAIT) in recent years were reviewed and their expressions in different thyroid diseases were also analyzed.
Results 　NIS proteins express at the basolateral membrane of thyrocytes in normal thyroid tissue, while pendrin and hAIT proteins are limited to the apical membrane of thyrocytes lining in the follicular lumen. In the tissues of thyroid carcinomas, it was found that the NIS proteins expressed in the cytoplasm and their expressions decreased; The mutation of NIS gene may be one of the main causes of congenital hypothyroidism. The expression of prendrin protein may be related to the function of follicles: its expression level increased significantly both in Graves diseases and toxic adenomas, but significantly decreased in differentiated thyroid carcinoma. However, the correlation between the decrease and the degrees of differentiation of carcinoma cell line are still disputable. The expression of hAIT protein does not significantly altered in hyperfunctioning tissues. It only slightly decreased occasionally in hypofunctioning adenomas, but it decreased significantly in thyroid carcinomas.
Conclusion 　The abnormal expressions of the three iodide transporters may be related closely with the type of thyroid diseases. However, their pathogenic mechanisms and the causes of their abnormal expression are still unknown, which need to be studied further.

Citation： ZHANG Heng,ZHU Jingqiang,LI Zhihui. Relation Between Iodide Transporters and Thyroid Diseases. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2007, 14(3): 376-379. doi: Copy

1.	Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter [J]. Nature， 1996; 379(6564)∶458.
2.	Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodium lodide symporter [J]. Biochem Biophys Res Commun， 1996; 226(2)∶39.
3.	Tazebay UH, Wapnir IL, Levy O, et al. The mammary gland iodide transporter is expressed during lactation and in breast cancer [J]. Nat Med， 2000; 6(8)∶871.
4.	Ohno M, Zannini M, Levy O, et al. The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription [J]. Mol Cell Biol， 1999; 19(3)∶2051.
5.	Riedel C, Levy O, Carrasco N. Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin [J]. J Biol Chem， 2001; 276(24)∶21458.
6.	Castro MR, Bergert ER, Beito TG, et al. Development of mo-noclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells [J]. J Clin Endocrinol Metab， 1999; 84(8)∶2957.
7.	Dohan O, Baloch Z, Banrevi Z, et al. Rapid communication: predominant intracellular overexpression of the Na(+)/I(-) symporter (NIS) in a large sampling of thyroid cancer cases [J]. J Clin Endocrinol Metab， 2001; 86(6)∶2697.
8.	Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, et al. The oncogene BRAF V600E 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 [J]. Endocr Relat Cancer， 2006; 13(1)∶257.
9.	Castro MR, Bergert ER, Goellner JR, et al. Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake [J]. J Clin Endocrinol Metab， 2001; 86(11)∶5627.
10.	Park HJ, Kim JY, Park KY, et al. Expressions of human sodium iodide symporter mRNA in primary and metastatic papillary thyroid carcinomas [J]. Thyroid， 2000; 10(3)∶211.
11.	Simon D, Korber C, Krausch M, et al. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study [J]. Eur J Nucl Med Mol Imaging， 2002; 29(6)∶775.
12.	Levy O, Ginter CS, De la Vieja A, et al. Identification of a structural requirement for thyroid Na+/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism [J]. FEBS Lett， 1998; 429(1)∶36.
13.	Dohan O, Gavrielides MV, Ginter C, et al. Na(+)/I(-) symporter activity requires a small and uncharged amino acid residue at position 395 [J]. Mol Endocrinol， 2002; 16(8)∶1893.
14.	Pohlenz J, Duprez L, Weiss RE, et al. Failure of membrane targeting causes the functional defect of two mutant sodium iodide symporters [J]. J Clin Endocrinol Metab， 2000; 85(7)∶2366.
15.	De La Vieja A, Ginter CS, Carrasco N. The Q267E mutation in the sodium/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number [J]. J Cell Sci， 2004; 117(Pt 5)∶677.
16.	De la Vieja A, Ginter CS, Carrasco N. Molecular analysis of a congenital iodide transport defect: G543E impairs maturation and trafficking of the Na+/I- ymporter [J]. Mol Endocrinol， 2005; 19(11)∶2847.
17.	Endo T, Kogai T, Nakazato M, et al. Autoantibody against Na+/I- symporter in the sera of patients with autoimmune thyroid disease [J]. Biochem Biophys Res Commun， 1996; 224(1)∶92.
18.	Seissler J, Wagner S, Schott M, et al. Low frequency of autoantibodies to the human Na(+)/I(-) symporter in patients with autoimmune thyroid disease [J]. J Clin Endocrinol Metab， 2000; 85(12)∶4630.
19.	Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS) [J]. Nat Genet， 1997; 17(4)∶411.
20.	Royaux IE, Suzuki K, Mori A, et al. Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells [J]. Endocrinology， 2000; 141(2)∶839.
21.	Scott DA, Wang R, Kreman TM, et al. The Pendred syndrome gene encodes a chloride-iodide transport protein [J]. Nat Genet， 1999; 21(4)∶440.
22.	Yoshida A, Taniguchi S, Hisatome I, et al. Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells [J]. J Clin Endocrinol Metab， 2002; 87(7）∶3356.
23.	Bidart JM, Mian C, Lazar V, et al. Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues [J]. J Clin Endocrinol Metab， 2000; 85(5)∶2028.
24.	Arturi F, Russo D, Bidart JM, et al. Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors [J]. Eur J Endocrinol, 2001; 145(2)∶129.
25.	Porra V, Bernier-Valentin F, Trouttet-Masson S, et al. Characterization and semiquantitative analyses of pendrin expressed in normal and tumoral human thyroid tissues [J]. J Clin Endocrinol Metab， 2002; 87(4)∶1700.
26.	Xing M, Tokumaru Y, Wu G, et al. Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis [J]. Cancer Res， 2003; 63(9)∶2312.
27.	Rodriguez AM, Perron B, Lacroix L, et al. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes [J]. J Clin Endocrinol Metab， 2002; 87(7)∶3500.
28.	Lacroix L, Pourcher T, Magnon C, et al. Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters [J]. J Clin Endocrinol Metab， 2004; 89(3)∶1423.
29.	Porra V, Ferraro-Peyret C, Durand C, et al. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas [J]. J Clin Endocrinol Metab， 2005; 90(5)∶3028.

1. Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter [J]. Nature， 1996; 379(6564)∶458.
2. Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodium lodide symporter [J]. Biochem Biophys Res Commun， 1996; 226(2)∶39.
3. Tazebay UH, Wapnir IL, Levy O, et al. The mammary gland iodide transporter is expressed during lactation and in breast cancer [J]. Nat Med， 2000; 6(8)∶871.
4. Ohno M, Zannini M, Levy O, et al. The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription [J]. Mol Cell Biol， 1999; 19(3)∶2051.
5. Riedel C, Levy O, Carrasco N. Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin [J]. J Biol Chem， 2001; 276(24)∶21458.
6. Castro MR, Bergert ER, Beito TG, et al. Development of mo-noclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells [J]. J Clin Endocrinol Metab， 1999; 84(8)∶2957.
7. Dohan O, Baloch Z, Banrevi Z, et al. Rapid communication: predominant intracellular overexpression of the Na(+)/I(-) symporter (NIS) in a large sampling of thyroid cancer cases [J]. J Clin Endocrinol Metab， 2001; 86(6)∶2697.
8. Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, et al. The oncogene BRAF V600E 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 [J]. Endocr Relat Cancer， 2006; 13(1)∶257.
9. Castro MR, Bergert ER, Goellner JR, et al. Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake [J]. J Clin Endocrinol Metab， 2001; 86(11)∶5627.
10. Park HJ, Kim JY, Park KY, et al. Expressions of human sodium iodide symporter mRNA in primary and metastatic papillary thyroid carcinomas [J]. Thyroid， 2000; 10(3)∶211.
11. Simon D, Korber C, Krausch M, et al. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study [J]. Eur J Nucl Med Mol Imaging， 2002; 29(6)∶775.
12. Levy O, Ginter CS, De la Vieja A, et al. Identification of a structural requirement for thyroid Na+/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism [J]. FEBS Lett， 1998; 429(1)∶36.
13. Dohan O, Gavrielides MV, Ginter C, et al. Na(+)/I(-) symporter activity requires a small and uncharged amino acid residue at position 395 [J]. Mol Endocrinol， 2002; 16(8)∶1893.
14. Pohlenz J, Duprez L, Weiss RE, et al. Failure of membrane targeting causes the functional defect of two mutant sodium iodide symporters [J]. J Clin Endocrinol Metab， 2000; 85(7)∶2366.
15. De La Vieja A, Ginter CS, Carrasco N. The Q267E mutation in the sodium/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number [J]. J Cell Sci， 2004; 117(Pt 5)∶677.
16. De la Vieja A, Ginter CS, Carrasco N. Molecular analysis of a congenital iodide transport defect: G543E impairs maturation and trafficking of the Na+/I- ymporter [J]. Mol Endocrinol， 2005; 19(11)∶2847.
17. Endo T, Kogai T, Nakazato M, et al. Autoantibody against Na+/I- symporter in the sera of patients with autoimmune thyroid disease [J]. Biochem Biophys Res Commun， 1996; 224(1)∶92.
18. Seissler J, Wagner S, Schott M, et al. Low frequency of autoantibodies to the human Na(+)/I(-) symporter in patients with autoimmune thyroid disease [J]. J Clin Endocrinol Metab， 2000; 85(12)∶4630.
19. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS) [J]. Nat Genet， 1997; 17(4)∶411.
20. Royaux IE, Suzuki K, Mori A, et al. Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells [J]. Endocrinology， 2000; 141(2)∶839.
21. Scott DA, Wang R, Kreman TM, et al. The Pendred syndrome gene encodes a chloride-iodide transport protein [J]. Nat Genet， 1999; 21(4)∶440.
22. Yoshida A, Taniguchi S, Hisatome I, et al. Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells [J]. J Clin Endocrinol Metab， 2002; 87(7）∶3356.
23. Bidart JM, Mian C, Lazar V, et al. Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues [J]. J Clin Endocrinol Metab， 2000; 85(5)∶2028.
24. Arturi F, Russo D, Bidart JM, et al. Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors [J]. Eur J Endocrinol, 2001; 145(2)∶129.
25. Porra V, Bernier-Valentin F, Trouttet-Masson S, et al. Characterization and semiquantitative analyses of pendrin expressed in normal and tumoral human thyroid tissues [J]. J Clin Endocrinol Metab， 2002; 87(4)∶1700.
26. Xing M, Tokumaru Y, Wu G, et al. Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis [J]. Cancer Res， 2003; 63(9)∶2312.
27. Rodriguez AM, Perron B, Lacroix L, et al. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes [J]. J Clin Endocrinol Metab， 2002; 87(7)∶3500.
28. Lacroix L, Pourcher T, Magnon C, et al. Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters [J]. J Clin Endocrinol Metab， 2004; 89(3)∶1423.
29. Porra V, Ferraro-Peyret C, Durand C, et al. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas [J]. J Clin Endocrinol Metab， 2005; 90(5)∶3028.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Relation Between Iodide Transporters and Thyroid Diseases

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