The importance of sodium/iodide symporter (NIS) for thyroid cancer management

The thyroid gland has the ability to uptake and concentrate iodide, which is a fundamental step in thyroid hormone biosynthesis. Radioiodine has been used as a diagnostic and therapeutic tool for several years. However, the studies related to the mechanisms of iodide transport were only possible after the cloning of the gene that encodes the sodium/iodide symporter (NIS). The studies about the regulation of NIS expression and the possibility of gene therapy with the aim of transferring NIS gene to cells that normally do not express the symporter have also become possible. In the majority of hypofunctioning thyroid nodules, both benign and malignant, NIS gene expression is maintained, but NIS protein is retained in the intracellular compartment. The expression of NIS in non-thyroid tumoral cells in vivo has been possible through the transfer of NIS gene under the control of tissue-specific promoters. Apart from its therapeutic use, NIS has also been used for the localization of metastases by scintigraphy or PET-scan with 124I. In conclusion, NIS gene cloning led to an important development in the field of thyroid pathophysiology, and has also been fundamental to extend the use of radioiodine for the management of non-thyroid tumors.     

脂质体介导人NIS基因转染肺癌A549细胞及其蛋白表达

目的 研究人钠/碘同向转运体(NIS)基因转染肺癌细胞及其蛋白表达.方法 鉴定质粒pcDAN3-hNIS中的插入基因NIS基因.培养的肺癌A549分为两组:实验组(转染pcDAN3-hNIS),对照组(转染pcDAN3).脂质体介导NIS基因转染肺癌细胞,采用Western Blot免疫印迹法和免疫组化法检测肺癌细胞中NIS蛋白的表达.结果 验组的肺癌细胞有NIS蛋白的表达,而对照组无表达,两组比较差异有显著性(P=0.000).结论 转染人NIS基因的肺癌细胞可表达NIS蛋白,为探索放射性碘治疗肺癌的研究提供理论依据.     

碘对大鼠体内及体外甲状腺钠碘转运体mRNA表达的调节

目的探讨碘过量对体内、体外甲状腺钠碘转运体（NIS）mRNA表达的影响。方法Wistar大鼠，随机分为低碘组（U）、适碘组（NI）、5倍高碘组（5HI）、10倍高碘组（10HI）、50倍高碘组（50HI）、100倍高碘组（100HI）．检测尿碘、甲状腺NISmRNA表达水平。FRTL细胞分别在含有10^-6-10^-3mol／L碘化钾的培养基中培养24、48h，检测NIS mRNA水平的变化。结果U组尿碘显著低于NI组，而甲状腺NIS mRNA表达水平明显高于NI组（P〈0．01）；各高碘组尿碘与NI组比较呈成倍升高．NISmRNA水平与NI组相比逐渐下降。FRTL细胞在分别含有10^-6—10^-3 mol／L碘化钾的培养基中培养24、48h．NIS mRNA的表达水平与对照组差异无统计学意义（P〉0．05）。结论碘对体内、体外甲状腺NIS mRNA表达的影响存在不同的机制，长期、慢性处于高碘摄入的大鼠主要通过转录水平影响甲状腺NIS mRNA的表达，而体外急性实验表明，高碘则可能通过转录后水平而起作用。     

Sodium/iodide symporter (NIS) and pendrin are expressed differently in hot and cold nodules of thyroid toxic multinodular goiter.

OBJECTIVE: The expression of two iodide transporters, the sodium/iodide symporter (NIS) and pendrin, was analyzed in thyroid tissues of patients with toxic multinodular goiter (TMNG) and non-toxic multinodular goiter (MNG). METHODS: The levels of NIS and pendrin proteins were analyzed in total protein extracts from nodular and non-nodular tissues by Western blot. RESULTS: In tissue samples from TMNG, we found an increased expression of NIS (2.5-fold) in the hot nodules, and similar levels between cold nodules and non-nodular tissues. In contrast, the levels of pendrin were slightly increased in both hot and cold nodules from TMNG, and decreased (about twofold) in cold nodules from MNG. We also noticed that there was no relationship between NIS and pendrin expression. CONCLUSIONS: Our data demonstrate that hot nodules from TMNG express a higher number of iodide transporters (mainly NIS), whereas cold nodules from TMNG, but not from MNG, show levels of the two proteins comparable with normal tissue, suggesting a role in vivo of TSH in maintaining the expression of NIS and pendrin protein in normal thyroid tissue. Finally, different mechanisms are involved in the regulation of NIS and pendrin expression.     

The sodium iodide symporter: its pathophysiological and therapeutic implications

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates the active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular lactating mammary gland. Because of its crucial role in the ability of thyroid follicular cells to trap iodide, cloning of NIS opened an exciting and extensive new field of thyroid-related research. Cloning and molecular characterization of NIS allowed investigation of its expression and regulation in thyroidal and nonthyroidal tissues, and its potential pathophysiological and therapeutic implications in benign and malignant thyroid disease. In addition to its key function in thyroid physiology, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as effective therapeutic application of radioiodine in benign and malignant thyroid disease. Characterization and application of NIS as a novel therapeutic gene and the presence of high native NIS expression in the majority of breast cancers further suggest a promising role of NIS in diagnosis and therapy of cancer outside the thyroid gland.     

Rarity of anti- Na+/I- symporter (NIS) antibody with iodide uptake inhibiting activity in autoimmune thyroid diseases (AITD)

The search for antibody against the Na+/I- symporter (NIS) has seen conflicting results over the years. Prior to cloning of NIS, Raspe et al found iodide uptake inhibiting sera were rare in autoimmune thyroid diseases (AITD) while post-cloning, others reported the presence of antibody in 12-15% of Hashimoto's thyroiditis (HT) and 30-84% of Graves' disease (GD). To evaluate the role of NIS as a potential antigen in AITD, a stable COS 7 cell line expressing high level of functional hNIS was established which allowed the screening of large number of sera for iodide uptake inhibiting activity in a 96-well plate format. Five hundred and fourteen serum samples taken from normal subjects and patients with AITD, non-autoimmune thyroid diseases, and non-thyroid autoimmune diseases were assayed for presence of iodide uptake inhibiting activity. Under the influence of these sera, iodide uptake showed a normal frequency distribution and diminution of uptake 2 SDs below the mean of controls was observed with 14 sera. Among these, 7 that were available for further study were re-evaluated after dialysis and/or Ig G extraction. All 7 sera lost their iodide uptake inhibiting activity, indicating that the effects were not antibody mediated and unknown serum factors had been responsible. In conclusion, contrary to previous results, the present study indicates that antibodies capable of modulating NIS activity are rare in AITD.     

Expression of the human sodium/iodide symporter (hNIS) in xenotransplanted human thyroid carcinoma.

The uptake of iodide in thyroid epithelial cells is mediated by the sodium/iodide symporter (NIS). The uptake of iodide is of vital importance for thyroid physiology and is a prerequisite for radioiodine therapy in thyroid cancer. Loss of iodide uptake due to diminished expression of the human NIS (hNIS) is frequently observed in metastasized thyroid cancer. So far, no animal model for the study of radioiodine therapy in thyroid cancer has been available. Strategies to restore iodide uptake in thyroid cancer include the exploration of hNIS gene transfer into hNIS defective thyroid cancer. We have performed a stable transfection of hNIS into the hNIS defective follicular thyroid carcinoma cell line FTC133. Stably transfected colonies exhibited high uptake of Na125I, which could be blocked completely with sodium perchlorate. hNIS transfected FTC133 and non-transfected cell lines injected subcutaneously in nude mice formed tumors after 6 weeks. Iodide uptake in the hNIS transfected tumor was much higher than in non-transfected tumor, but a rapid release of radioactivity from the hNIS transfected tumor was observed. Further studies are necessary to investigate the role of hNIS in relation to other thyroid specific proteins in iodide metabolism in thyroid cancer.     

Autoimmunity involving the human sodium/iodide symporter: fact or fiction?

Presence, functional activity and clinical relevance of autoantibodies directed against the human sodium iodide symporter (NIS) in thyroid autoimmune diseases have become the subject of much controversy in recent years. Earlier reports have claimed that NIS may represent a major thyroid autoantigen that elicits formation of functionally relevant autoantibodies in a significant proportion of patients with Graves' disease (GD) and Hashimoto's thyroiditis (HT). Moreover, a recent study has extended this notion by reporting detection of NIS-autoantibodies in 22% and 24% of a small number of patients with GD and HT, respectively, but not in patients with other autoimmune diseases. However, in striking contrast to these reports, two independent groups of investigators have now presented convincing evidence that NIS-directed autoantibodies occur with low frequency among a large sample of patients with autoimmune thyroid diseases. Moreover, no evidence of specific iodide uptake inhibiting activity was obtained once sera had been subjected to dialysis and/or IgG extraction. Thus, although the controversy has not been definitively resolved, hNIS does not appear to be a major functionally relevant antigen in autoimmune thyroid diseases. Moreover, when detected in addition to TPO and TSH receptor autoantibodies, NIS-directed autoantibodies do not appear to contribute any diagnostic power for GD and HT.     

Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells

The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of beta-emitting radioiodide-131 ((131)I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance (131)I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) beta/gamma produced marked NIS induction; and selective stimulation of RARalpha, RARgamma, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR beta/gamma-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC(50) of tRA for NIS stimulation to approximately 7%, such that 10(-7) m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of (131)I greater than 10(-6) m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of (131)I after combination treatment.