Regulation of the sodium iodide symporter by iodide in FRTL-5 cells

OBJECTIVE: The acute decrease in iodide organification in the thyroid in response to excess iodide is termed the acute Wolff-Chaikoff effect and normal organification resumes in spite of continued high plasma iodide concentrations (escape from the acute Wolff-Chaikoff effect). We have recently reported that large doses of iodide given to rats chronically decrease the sodium/iodide symporter (NIS) mRNA and protein, suggesting that escape is due to a decrease in NIS and subsequent iodide transport. We have now studied the effect of excess iodide on NIS in FRTL-5 cells to further explore the mechanisms whereby excess iodide decreases NIS. DESIGN: FRTL-5 cells were employed and were incubated in the presence or absence of various concentrations of iodide. NIS mRNA and protein and the turnover of NIS were assessed. METHODS: NIS mRNA was measured by Northern analysis, NIS protein by Western analysis and NIS turnover by pulse-chase labeling experiments. RESULTS: Iodide (10(-) mol/l) had no effect on NIS mRNA in FRTL-5 cells at 24 and 48 h compared with cells cultured in the absence of iodide. However, excess iodide decreased NIS protein by 50% of control values at 24 h and by 70% at 48 h. This effect of iodide was dose dependent. Pulse-chase experiments demonstrated that there was no effect of iodide on new NIS protein synthesis and that the turnover of NIS protein in the presence of iodide was 27% faster than in the absence of added iodide. CONCLUSIONS: Excess iodide does not decrease NIS mRNA in FRTL-5 cells but does decrease NIS protein, suggesting that in this in vitro thyroid cell model iodide modulates NIS, at least in part, at a post-transcriptional level. This iodide-induced decrease in NIS protein appears to be due, at least partially, to an increase in NIS protein turnover.

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A Homozygous Missense Mutation of the Sodium/Iodide Symporter Gene Causing Iodide Transport Defect1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.12.4425 ◽

1997 ◽

Vol 82 (12) ◽

pp. 3966-3971

Author(s):

Akira Matsuda ◽

Shinji Kosugi

Keyword(s):

Missense Mutation ◽

Ribonucleic Acid ◽

Sodium Iodide ◽

Northern Analysis ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Complementary Dna ◽

Homozygous Missense Mutation ◽

Iodide Transport ◽

Nis Gene

Iodide transport defect is a disorder characterized by an inability of the thyroid to maintain an iodide concentration difference between the plasma and the thyroid. The recent cloning of the sodium/iodide symporter (NIS) gene enabled us to characterize the NIS gene in this disorder. We identified a homozygous missense mutation of A→C at nucleotide +1060 in NIS complementary DNA in a male patient who was born from consanguineous marriage, had a huge goiter, and lacked the ability to accumulate iodide but was essentially euthyroid. The mutation results in an amino acid replacement of Thr354→Pro in the middle of the ninth transmembrane domain. COS-7 cells transfected with the mutant NIS complementary DNA showed markedly decreased iodide uptake, confirming that this mutation was the direct cause of the disorder in the patient. Northern analysis of thyroid ribonucleic acid revealed that NIS messenger ribonucleic acid level was markedly increased (>100-fold) compared with that in the normal thyroid, suggesting possible compensation by overexpression.

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Sodium-Iodide Symporter Mediates Iodide Secretion in Rat Gastric Mucosa In Vitro

Experimental Biology and Medicine ◽

10.1177/153537020623100306 ◽

2006 ◽

Vol 231 (3) ◽

pp. 277-281 ◽

Cited By ~ 12

Author(s):

Malin Josefsson ◽

Lena Evilevitch ◽

Björn Weström ◽

Torsten Grunditz ◽

Eva Ekblad

Keyword(s):

Gastric Mucosa ◽

Sodium Iodide ◽

Sodium Perchlorate ◽

Nitric Oxide Donor ◽

Sodium Iodide Symporter ◽

Iodide Transport ◽

Gastric Lumen ◽

Rat Gastric Mucosa ◽

Mucosal Side

In vivo studies on rats have demonstrated that considerable amounts of iodide are transported from the bloodstream into the gastric lumen. The mechanisms for and functional significance of this transport are poorly understood. Active (driven by Na+/K+-ATPase) iodide transport into thyroid follicular cells is mediated by the sodium-iodide symporter (NIS), which is also abundantly expressed in gastric mucosa. We aimed to further investigate the iodide transport in gastric mucosa and the Possible role of NIS in this transport process. Iodide transport in rat gastric mucosa was studied in vitro in an Ussing chamber system using 125I as a marker. The system allows measurements in both directions over a mucosal specimen. A considerable transport of iodide (from the serosal to the mucosal side) was established across the gastric mucosa, whereas in the opposite direction (mucosa to serosa), iodide transport was negligible. Sodium Perchlorate (NaClO4), a competitive inhibitor of NIS, and ouabain, an inhibitor of the Na+/K+-ATPase, both attenuated gastric iodide transport from the serosal to the mucosal side. To investigate a possible neuroendocrine regulation of the iodide transport identified to occur from the serosal to the mucosal side of the stomach, thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP), histamine, or nitric oxide donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) was added. None of these substances influenced the iodide transport. We conclude that iodide is actively transported into the gastric lumen and that this transport is at least partly mediated by NIS. Additional investigations are needed to understand the regulation and significance of this transport.

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99mTc reduziert nach intrazellulärer Aufnahme in NIS-positiven Zellen in vitro das klonogene Überleben stärker als 131I

Nuklearmedizin ◽

10.3413/nukmed-0300 ◽

2010 ◽

Vol 49 (04) ◽

pp. 154-160 ◽

Cited By ~ 9

Author(s):

M. Wendisch ◽

R. Freudenberg ◽

J. Drechsel ◽

R. Runge ◽

G. Wunderlich ◽

...

Keyword(s):

Sodium Iodide ◽

Diagnostic Procedures ◽

Dose Effect ◽

Thyroid Cell ◽

Sodium Iodide Symporter ◽

Auger Electrons ◽

Beta Emitter ◽

Path Lengths ◽

Colony Forming Assay

Summary Aim: In addition to gamma radiation of 140 keV 99mTc emits during the transition to 99Tc electrons of low energy and tiny path-lengths. These Auger electrons cannot be utilized in diagnostic procedures. However, they were discussed frequently for therapeutic application. Hitherto proof of effect of the Auger electrons from 99mTc is missing which is supplied now in an in vitro-system in comparison to beta-emitter 131I. Methods: The thyroid cell line PC Cl3 (sodium iodide symporter (NIS)-positive) was incubated with 131I-sodium iodide (131I) or 99mTc-pertechnetate (99mTc) in presence or absence of perchlorate. For comparison the amount of radioactivity was adjusted to obtain the same dose from extracellular irradiation for both radionuclides. The colony forming assay detects the clonogenic cell survival as surviving fraction. In addition, intracellular radionuclide uptake was quantified. Results: Dose effect curves were established for 131I and 99mTc for variable extra- and intracellular distribution of the radioactivity. In presence of perchlorate no cellular uptake of radioactivity was detectable. Survival curves were largely comparable confirming the dosimetric calculations. In absence of perchlorate cellular radiotracer uptake varied from 1.39% (131I) to 1.90% 99mTc). Effects on survival were twice for the beta-emitter and ten-fold higher for 99mTc. Conclusions: Intracellular uptake of 131I and 99mTc increases DNA-damage compared to strict extracellular radiotracer distribution which was demonstrated by means of colony forming assay. Increasing radiotoxicity from intracellular 99mTc is explained most likely by increased dose deposition in cellular structures due to Auger- and conversion-electrons of low range and high local energy deposition.

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

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302007000500004 ◽

2007 ◽

Vol 51 (5) ◽

pp. 672-682 ◽

Cited By ~ 36

Author(s):

Denise P. Carvalho ◽

Andrea C.F. Ferreira

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Therapeutic Tool ◽

Iodide Transport ◽

Cancer Management ◽

Thyroid Hormone Biosynthesis ◽

Nis Gene ◽

Hormone Biosynthesis ◽

Tumoral Cells

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.

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Mediator complex subunit 16 is down-regulated in papillary thyroid cancer, leading to increased transforming growth factor-β signaling and radioiodine resistance

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012404 ◽

2020 ◽

Vol 295 (31) ◽

pp. 10726-10740

Author(s):

Hongwei Gao ◽

Peirong Bai ◽

Lin Xiao ◽

Mengjia Shen ◽

Qiuxiao Yu ◽

...

Keyword(s):

Cell Migration ◽

Thyroid Cancer ◽

Growth Factor ◽

Sodium Iodide ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Mediator Complex ◽

Papillary Thyroid ◽

Sodium Iodide Symporter

Mediator complex subunit 16 (MED16) is a component of the mediator complex and functions as a coactivator in transcriptional events at almost all RNA polymerase II–dependent genes. In this study, we report that the expression of MED16 is markedly decreased in papillary thyroid cancer (PTC) tumors compared with normal thyroid tissues. In vitro, MED16 overexpression in PTC cells significantly inhibited cell migration, enhanced sodium/iodide symporter expression and iodine uptake, and decreased resistance to radioactive 131I (RAI). Conversely, PTC cells in which MED16 had been further knocked down (MED16KD) exhibited enhanced cell migration, epithelial–mesenchymal transition, and RAI resistance, accompanied by decreased sodium/iodide symporter levels. Moreover, cell signaling through transforming growth factor β (TGF-β) was highly activated after the MED16 knockdown. Similar results were obtained in MED12KD PTC cells, and a co-immunoprecipitation experiment verified interactions between MED16 and MED12 and between MED16 and TGF-βR2. Of note, the application of LY2157299, a potent inhibitor of TGF-β signaling, significantly attenuated MED16KD-induced RAI resistance both in vitro and in vivo. In conclusion, our findings indicate that MED16 reduction in PTC contributes to tumor progression and RAI resistance via the activation of the TGF-β pathway.

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Dual inhibition of BRAF and MEK increases expression of sodium iodide symporter in patient-derived papillary thyroid cancer cells in vitro

Surgery ◽

10.1016/j.surg.2019.04.076 ◽

2020 ◽

Vol 167 (1) ◽

pp. 56-63 ◽

Cited By ~ 2

Author(s):

Timothy M. Ullmann ◽

Heng Liang ◽

Maureen D. Moore ◽

Isra Al-Jamed ◽

Katherine D. Gray ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Papillary Thyroid Cancer ◽

Sodium Iodide ◽

Papillary Thyroid ◽

Sodium Iodide Symporter ◽

Dual Inhibition ◽

Thyroid Cancer Cells

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The Effect on Sodium/Iodide Symporter and Pendrin in Thyroid Colloid Retention Developed by Excess Iodide Intake

Biological Trace Element Research ◽

10.1007/s12011-015-0580-4 ◽

2015 ◽

Vol 172 (1) ◽

pp. 193-200 ◽

Cited By ~ 5

Author(s):

Xiao-yi Chen ◽

Chu-hui Lin ◽

Li-hua Yang ◽

Wang-gen Li ◽

Jin-wei Zhang ◽

...

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Colloid Retention ◽

Excess Iodide ◽

Thyroid Colloid

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Evaluation of Lentiviral-Mediated Expression of Sodium Iodide Symporter in Anaplastic Thyroid Cancer and the Efficacy of In Vivo Imaging and Therapy

Journal of Oncology ◽

10.1155/2011/178967 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Chien-Chih Ke ◽

Ya-Ju Hsieh ◽

Luen Hwu ◽

Fu-Hui Wang ◽

Fu-Du Chen ◽

...

Keyword(s):

Gene Expression ◽

Sodium Iodide ◽

Cell Function ◽

Tumor Imaging ◽

Promising Result ◽

Anaplastic Thyroid Cancer ◽

Anaplastic Thyroid Carcinoma ◽

Sodium Iodide Symporter

Anaplastic thyroid carcinoma (ATC) is one of the most deadly cancers. With intensive multimodalities of treatment, the survival remains low. ATC is not sensitive to131I therapy due to loss of sodium iodide symporter (NIS) gene expression. We have previously generated a stable human NIS-expressing ATC cell line, ARO, and the ability of iodide accumulation was restored. To make NIS-mediated gene therapy more applicable, this study aimed to establish a lentiviral system for transferring hNIS gene to cells and to evaluate the efficacy of in vitro and in vivo radioiodide accumulation for imaging and therapy. Lentivirus containing hNIS cDNA were produced to transduce ARO cells which do not concentrate iodide. Gene expression, cell function, radioiodide imaging and treatment were evaluated in vitro and in vivo. Results showed that the transduced cells were restored to express hNIS and accumulated higher amount of radioiodide than parental cells. Therapeutic dose of131I effectively inhibited the tumor growth derived from transduced cells as compared to saline-treated mice. Our results suggest that the lentiviral system efficiently transferred and expressed hNIS gene in ATC cells. The transduced cells showed a promising result of tumor imaging and therapy.

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Decreased Expression of Thyroglobulin and Sodium Iodide Symporter Genes in Hashimoto’s Thyroiditis

International Journal of Endocrinology ◽

10.1155/2014/690704 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Anna Popławska-Kita ◽

Beata Telejko ◽

Katarzyna Siewko ◽

Maria Kościuszko-Zdrodowska ◽

Natalia Wawrusewicz-Kurylonek ◽

...

Keyword(s):

Mrna Expression ◽

Hashimoto’S Thyroiditis ◽

Sodium Iodide ◽

Interleukin 1 ◽

Thyroid Volume ◽

Needle Aspiration ◽

Hashimoto's Thyroiditis ◽

Sodium Iodide Symporter ◽

Thyroid Cells ◽

Iodide Transport

Aim. The aim of the study was to compare the expression of sodium iodide symporter (NIS), thyroglobulin (Tg), tumor necrosis factor-α(TNFα), and interleukin-1βgenes in patients with Hashimoto’s thyroiditis (HT) and healthy individuals.Subjects and Methods.Thyroid cells were obtained from 39 patients with HT and 15 controls by an ultrasound guided fine needle aspiration biopsy.Results. The patients with HT had lower Tg and NIS mRNA (P=0.002andP=0.001, resp.), as well as higher TNFαmRNA expression (P=0.049) than the controls. In the HT group Tg mRNA expression correlated positively with NIS mRNA expression (R=0.739,P=0.0001) and thyroid volume (R=0.465,P=0.0005), as well as negatively with TNFαmRNA expression (R=-0.490,P=0.001) and anti-peroxidase antibodies (TPOAb) level (R=-0.482,P=0.0002), whereas NIS mRNA expression correlated positively with thyroid volume (R=0.319,P=0.02), as well as negatively with TNFαmRNA expression (R=-0.529,P=0.0006) and TPOAb level (R=-0.422,P=0.001).Conclusions.Our results suggest that decreased Tg and NIS expression in thyroid cells may result in reduced active iodide transport and reduced thyroid volume in patients with HT.

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