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1
Elliyanti, Aisyah, Rony Rustam, Tofrizal Tofrizal, Yenita Yenita, and Yayi D. Billianti Susanto. "Evaluating the Natrium Iodide Symporter Expressions in Thyroid Tumors." Open Access Macedonian Journal of Medical Sciences 9, B (January 5, 2021): 18–23. http://dx.doi.org/10.3889/oamjms.2021.5534.
Анотація:
BACKGROUND: Decreased Natrium iodide symporter (NIS) expression levels or diminished NIS targeting thyroid cancer cells’ plasma membrane leads to radioiodine-refractory disease.
AIM: The aim of this study was to analyze the NIS expression in thyroid tumors.
MATERIALS AND METHODS: The samples were thyroid tissues of patients who underwent surgery for a thyroid tumor. The tissues were processed for NIS protein expressions by immunohistochemistry (IHC) and Western blot (WB). Graves’ disease samples were used as positive controls. The samples were incubated without the primary antibody, and they were used as negative controls for IHC examination. Na+/K+ ATPase was a plasma membrane protein marker in the WB procedure.
RESULTS: Twenty-nine samples were assessed for NIS protein. All of them showed the expression in the cytoplasm with intensity 1+ to 3+ with Allred score 3-8. Fourteen out of 29 cases (48.2%) showed NIS cytoplasm staining intensity ≥2+ consist of 10 papillary thyroid cancer (PTC), three follicular thyroid cancer, and one adenoma. Membrane staining was found in 2 samples of PTC (6.9%). Six samples (adenoma 1 sample, PTC 5 samples) showed NIS expression at membrane very weak (1+); they were considered as negative. NIS protein has several bands of ~ 80 kDa, ~ 62 kDa, and ~ 49 kDa.
CONCLUSION: NIS expression in thyroid cancer mostly expresses in the cytoplasm instead of the membrane. NIS will play a functional role in the membrane to bring iodine across the membrane against the concentration. It can be the main reason for the lack of response of radioiodine in some differentiated thyroid cancers.
2
Elliyanti, Aisyah, Tenny Putri Wikayani, Noormartany, Johan S. Masjhur, and Tri Hanggono Achmad. "Deteksi Natrium/Iodide Symporter (NIS) pada Galur Sel Kanker Payudara SKBR3 dengan Imunositofluoresens." Majalah Kedokteran Bandung 48, no. 1 (2016): 15–18. http://dx.doi.org/10.15395/mkb.v48n1.728.
3
Elliyanti, Aisyah. "Deteksi Natrium/Iodide Symporter (NIS) pada Galur Sel Kanker Payudara SKBR3 dengan Imunositofluoresens." Majalah Kedokteran Bandung 48, no. 1 (2016): 15–18. http://dx.doi.org/10.15395/mkb.v48n1.728.1.
4
Elliyanti, Aisyah, Tenny Putri Wikayani, Noormartany, Johan S. Masjhur, and Tri Hanggono Achmad. "Deteksi Natrium/Iodide Symporter (NIS) pada Galur Sel Kanker Payudara SKBR3 dengan Imunositofluoresens." Majalah Kedokteran Bandung 48, no. 1 (March 2016): 15–18. http://dx.doi.org/10.15395/mkb.v48n1.729.
5
Elliyanti, Aisyah, Andani Eka Putra, Yunia Sribudiani, Noormartany Noormartany, Johan S. Masjhur, Tri Hanggono Achmad, and Dachriyanus Dachriyanus. "Epidermal Growth Factor and Adenosine Triphosphate Induce Natrium Iodide Symporter Expression in Breast Cancer Cell Lines." Open Access Macedonian Journal of Medical Sciences 7, no. 13 (August 6, 2019): 2088–92. http://dx.doi.org/10.3889/oamjms.2019.620.
Анотація:
AIM: This study aims to investigate the effect of ATP, EGF and combination of those two to the Natrium Iodide Symporter (NIS) expression in MCF7, SKBR3 and HaCaT cell lines.
METHODS: MCF7, SKBR3 and HaCaT cell lines were treated with ATP, EGF and combination of those two for 6, 12 and 24 hours. The expression of NIS mRNA was measured through quantitative-reverse transcription-polymerase chain reaction (qRT-PCR). The NIS protein expression was confirmed by immunocytofluorescence.
RESULTS: NIS mRNA was expressed in SKBR3 and HaCaT cell lines but not in MCF7. The levels of NIS mRNA expression, after treatment by epidermal growth factor (EGF), adenosine Tri-Phosphate (ATP) or the combination of both for 6 and 12 hours were not significantly different from those of untreated cells. However, the treatment by a combination of ATP and EGF for 24 hours increases the level of NIS mRNA expression by 1.6 fold higher than that of the untreated cells (1.6241 ± 0.3, p < 0.05) and protein NIS expression increase significantly by the treatment than untreated cells (P < 0.05).
CONCLUSION: The level of NIS expression varies among the different subtypes of breast cancer cell lines. MCF7 cell line is representing the luminal A subtype of breast cancer does not express NIS. Only SKBR3 cell line express NIS and this subtype might be suitable to receive radioiodine therapy as those cells expressing NIS. A combination treatment of EGF and ATP increases the expression of NIS mRNA and protein at the membrane in SKBR3 cells.
6
Spitzweg, C. "Der Natrium-Iodid-Symporter (NIS): Bedeutung für die Bildgebung und therapeutische Optionen." Der Nuklearmediziner 30, no. 1 (March 2007): 19–30. http://dx.doi.org/10.1055/s-2006-955219.
7
Lisco, Giuseppe, Anna De Tullio, Vito Angelo Giagulli, Giovanni De Pergola, and Vincenzo Triggiani. "Interference on Iodine Uptake and Human Thyroid Function by Perchlorate-Contaminated Water and Food." Nutrients 12, no. 6 (June 4, 2020): 1669. http://dx.doi.org/10.3390/nu12061669.
Анотація:
Background: Perchlorate-induced natrium-iodide symporter (NIS) interference is a well-recognized thyroid disrupting mechanism. It is unclear, however, whether a chronic low-dose exposure to perchlorate delivered by food and drinks may cause thyroid dysfunction in the long term. Thus, the aim of this review was to overview and summarize literature results in order to clarify this issue. Methods: Authors searched PubMed/MEDLINE, Scopus, Web of Science, institutional websites and Google until April 2020 for relevant information about the fundamental mechanism of the thyroid NIS interference induced by orally consumed perchlorate compounds and its clinical consequences. Results: Food and drinking water should be considered relevant sources of perchlorate. Despite some controversies, cross-sectional studies demonstrated that perchlorate exposure affects thyroid hormone synthesis in infants, adolescents and adults, particularly in the case of underlying thyroid diseases and iodine insufficiency. An exaggerated exposure to perchlorate during pregnancy leads to a worse neurocognitive and behavioral development outcome in infants, regardless of maternal thyroid hormone levels. Discussion and conclusion: The effects of a chronic low-dose perchlorate exposure on thyroid homeostasis remain still unclear, leading to concerns especially for highly sensitive patients. Specific studies are needed to clarify this issue, aiming to better define strategies of detection and prevention.
8
Perone, Denise, Silvânia S. Teixeira, Sueli A. Clara, Daniela C. dos Santos, and Célia R. Nogueira. "Aspectos genéticos do hipotireoidismo congênito." Arquivos Brasileiros de Endocrinologia & Metabologia 48, no. 1 (February 2004): 62–69. http://dx.doi.org/10.1590/s0004-27302004000100008.
Анотація:
Hipotireoidismo congênito (HC) afeta cerca de 1:3000 a 1:4000 recém-nascidos (RN). Numerosos genes são essenciais, tanto para o desenvolvimento normal do eixo hipotálamo-hipófise-tireóide quanto para a produção hormonal, e estão associados ao HC. Cerca de 85% do hipotireoidismo primário é denominado disgenesia tireoidiana e evidências sugerem que mutações nos fatores de transcrição (TTF2, TTF1 e PAX-8) e no gene do receptor de TSH podem ser responsáveis pela doença. Os defeitos hereditários da síntese hormonal podem ser devidos a mutações nos genes NIS (natrium-iodide symporter), pendrina, tireoglobulina (TG), peroxidase (TPO). Mais recentemente, mutações no gene THOX-2 têm sido descritas para defeitos na organificacão. O hipotireoidismo central afeta cerca de 1:20.000 RN e tem sido associado com mutações nos fatores transcricionais hipofisários (POUIF1, PROP1, LHX3, HESX1). A síndrome de resistência periférica ao hormônio tireoidiano é uma doença rara que cursa com hipotireoidismo em alguns tecidos e, freqüentemente, está associada a mutações autossômicas dominantes no receptor beta (TRß).
9
Spitzweg, C. "Der Natrium-Jodid-Symporter (NIS)." Der Internist 44, no. 4 (March 4, 2003): 396–411. http://dx.doi.org/10.1007/s00108-003-0877-9.
10
Van Sande, J., C. Massart, R. Beauwens, A. Schoutens, S. Costagliola, J. E. Dumont, and J. Wolff. "Anion Selectivity by the Sodium Iodide Symporter." Endocrinology 144, no. 1 (January 1, 2003): 247–52. http://dx.doi.org/10.1210/en.2002-220744.
Анотація:
Abstract The iodide transporter of the thyroid (NIS) has been cloned by the group of Carrasco. The NIS-mediated transport was studied by electrophysiological methods in NIS-expressing Xenopus oocytes. Using this method, the anion selectivity of NIS was different from that previously reported for thyroid cells, whereas perchlorate and perrhenate were found not transported. In this study we compared the properties of human NIS, stably transfected in COS-7 cells to those of the transport in a thyroid cell line, the FRTL5 cells, by measuring the transport directly. We measured the uptake of 125I−, 186ReO4−, and 99mTcO4− and studied the effect on it of known competing anions, i.e. ClO4−, SCN−, ClO3−, ReO4−, and Br−. We conclude that the properties of the NIS transporter account by themselves for the properties of the thyroid iodide transporter as described previously in thyroid slices. The order of affinity was: ClO4− > ReO4− > I− ≥ SCN− > ClO3− > Br−. NIS is also inhibited by dysidenin (as in dog thyroid).
11
Schumm-Draeger, P. M. "Sodium/iodide symporter (NIS) and cytokines." Experimental and Clinical Endocrinology & Diabetes 109, no. 01 (December 31, 2001): 32–34. http://dx.doi.org/10.1055/s-2001-11018.
12
Lindenthal, Sabine, Nathalie Lecat-Guillet, Alejandro Ondo-Mendez, Yves Ambroise, Bernard Rousseau, and Thierry Pourcher. "Characterization of small-molecule inhibitors of the sodium iodide symporter." Journal of Endocrinology 200, no. 3 (December 3, 2008): 357–65. http://dx.doi.org/10.1677/joe-08-0246.
Анотація:
The sodium/iodide symporter (NIS) mediates the active transport of iodide from the bloodstream into thyrocytes. NIS function is strategic for the diagnosis and treatment of various thyroid diseases. In addition, a promising anti-cancer strategy based on targeted NIS gene transfer in non-thyroidal cells is currently developed. However, only little information is available concerning the molecular mechanism of NIS-mediated iodide translocation. Ten small molecules have recently been identified using a high-throughput screening method for their inhibitory effect on iodide uptake of NIS-expressing mammalian cells. In the present study, we analyzed these compounds for their rapid and reversible effects on the iodide-induced current in NIS-expressing Xenopus oocytes. Four molecules almost completely inhibited the iodide-induced current; for three of them the effect was irreversible, for one compound the initial current could be fully re-established after washout. Three molecules showed a rapid inhibitory effect of about 75%, half of which was reversible. Another three compounds inhibited the iodide-induced current from 10 to 50%. Some molecules altered the membrane conductance by themselves, i.e. in the absence of iodide. For one of these molecules the observed effect was also found in water-injected oocytes whereas for some others the iodide-independent effect was associated with NIS expression. The tested molecules show a surprisingly high variability in their possible mode of action, and thus are promising tools for further functional characterization of NIS on a molecular level, and they could be useful for medical applications.
13
Arturi, Franco, Diego Russo, Martin Schlumberger, Jean-Antoine du Villard, Bernard Caillou, Paolo Vigneri, René Wicker, Eusebio Chiefari, Horacio G. Suarez, and Sebastiano Filetti. "Iodide Symporter Gene Expression in Human Thyroid Tumors1." Journal of Clinical Endocrinology & Metabolism 83, no. 7 (July 1, 1998): 2493–96. http://dx.doi.org/10.1210/jcem.83.7.4974.
Анотація:
Expression of the Na+/I− symporter (NIS) gene was investigated by RT-PCR in a selected series of 26 primary thyroid carcinomas (19 papillary, 5 follicular, and 2 anaplastic). Fifteen follicular adenomas (11 “cold ” and 4 “hot” adenomas) were also studied. Five of 19 papillary thyroid cancer did not express NIS messenger ribonucleic acid (mRNA). In all but 1 follicular cancer, NIS transcript was fully detected. In anaplastic tissue, NIS mRNA was only barely detected in 1 case. All of the follicular thyroid adenomas except 1 expressed the NIS gene. In contrast, all tumors studied excluding the anaplastic histotype fully expressed thyroglobulin and thyroid peroxidase mRNA transcripts. In 2 patients, a lower expression (3- to 5-fold) of NIS mRNA was found in metastasis by dot blot analysis compared with those in both normal and primary neoplastic thyroid tissue. Four of 8 differentiated thyroid cancer patients selected for the presence of metastases with negative posttherapy 131I total body scan showed the lack of NIS gene expression in their primary cancer. This defect, at least in these cases, is a somatic and intrinsic lesion of the primary cancer cells and is not due to a dedifferentiation process in the metastatic tissue. The early detection of the loss of NIS gene expression in the primary cancer, therefore, may provide useful information for the management of differentiated thyroid cancer patients.
14
Li, Huika, Kerry Richard, Brett McKinnon, and Robin H. Mortimer. "Effect of Iodide on Human Choriogonadotropin, Sodium-Iodide Symporter Expression, and Iodide Uptake in BeWo Choriocarcinoma Cells." Journal of Clinical Endocrinology & Metabolism 92, no. 10 (October 1, 2007): 4046–51. http://dx.doi.org/10.1210/jc.2006-2358.
Анотація:
Abstract Context: Active placental transport of maternal iodide by the thyroidal sodium iodide symporter (NIS) provides an essential substrate for fetal thyroid hormone synthesis. NIS is expressed in trophoblast and is regulated by human choriogonadotropin (hCG). In thyroid, iodide down-regulates expression of several genes including NIS. Placentas of iodine-deficient rats demonstrate up-regulation of NIS mRNA, suggesting a role for iodide in regulating placental NIS. Objectives and Methods: The objectives were to examine effects of iodide on expression of NIS and hCG in BeWo choriocarcinoma cells. Gene expression was studied by quantitative real-time PCR. Effects on NIS protein expression were assessed by Western blotting. Functional activity of NIS was measured by 125I uptake. Expression of hCG protein was assessed by immunoassay of secreted hormone. Results: Iodide inhibited NIS mRNA and membrane protein expression as well as 125I uptake, which were paralleled by decreased βhCG mRNA expression and protein secretion. Iodide had no effects on pendrin expression. Addition of hCG increased NIS mRNA expression. This effect was partially inhibited by addition of iodide. The inhibitory effects of iodide on NIS mRNA expression were abolished by propylthiouracil and dithiothreitol. Conclusions: We conclude that expression of placental NIS is modulated by maternal iodide. This may occur through modulation of hCG effects on NIS and hCG gene expression.
15
Knapp, W. H., E. Pötter, and T. Petrich. "Functional activity of human sodium/iodide symporter in tumor cell lines." Nuklearmedizin 42, no. 01 (2003): 15–18. http://dx.doi.org/10.1055/s-0038-1623900.
Анотація:
Summary Aim: The sodium/iodide symporter (NIS) actively transports iodide into thyrocytes. Thus, NIS represents a key protein for diagnosis and radioiodine therapy of differentiated thyroid cancer. Additionally, in the future the NIS gene may be used for cancer gene therapy of non-thyroid-derived malignancies. In this study we evaluated the functionality of NIS with respect to iodide uptake in a panel of tumor cell lines and compared this to gene transfer efficiency. Methods: A human NIS-containing expression vector and reporter-gene vectors encoding ß-Galactosidase- or EGFP were used for transient transfection of 13 tumor cell lines. Following transfection measurements of NIS-mediated radioiodide uptake using Na125I and of transfection efficiency were performed. The latter included ß-Galactosidase activity measurements using a commercial kit and observation by fluorescence microscopy for EGFP expression. Results: In contrast to respective parental cells, most NIS-transfected cell lines displayed high, perchlorate-sensitive radioiodide uptake. Differences in radioiodide uptake between cell lines apparently corresponded to transfection efficiencies, as judged from reporter-gene assays. Conclusion: With respect to iodide uptake we provide evidence that NIS is functional in different cellular context. As iodide uptake capacity appears to be well correlated to gene transfer efficiency, cell type-specific actions on NIS (e. g. post-translational modification such as glycosylation) are not inhibitory to NIS function. Our data support the promising role of NIS in cancer gene therapy strategies.
16
Kogai, T., K. Taki, and G. A. Brent. "Enhancement of sodium/iodide symporter expression in thyroid and breast cancer." Endocrine-Related Cancer 13, no. 3 (September 2006): 797–826. http://dx.doi.org/10.1677/erc.1.01143.
Анотація:
The sodium/iodide symporter (NIS) mediates iodide uptake in the thyroid gland and lactating breast. NIS mRNA and protein expression are detected in most thyroid cancer specimens, although functional iodide uptake is usually reduced resulting in the characteristic finding of a ‘cold’ or non-functioning lesion on a radioiodine image. Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated thyroid cancer to utilize β-emitting radioactive iodide for the treatment of residual and metastatic disease. Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma membrane, increasing radioiodide uptake. Approximately 10–20% differentiated thyroid cancers, however, do not express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis. Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer specimens, but the fraction with functional iodide transport is relatively low. Lactogenic hormones and various nuclear hormone receptor ligands increase iodide uptake in breast cancer cells in vitro, but TSH has no effect. A wide range of ‘differentiation’ agents have been utilized to stimulate NIS expression in thyroid and breast cancer using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in ‘scan-negative’ thyroid cancer and some breast cancer.
17
Riesco-Eizaguirre, Garcilaso, Pilar Santisteban, and Antonio De la Vieja. "The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues." Endocrine-Related Cancer 28, no. 10 (October 1, 2021): T141—T165. http://dx.doi.org/10.1530/erc-21-0217.
Анотація:
The sodium/iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years, radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression, and the role that miRNAs play in fine-tuning NIS after being transcribed. A review on how hormones, cytokines, and iodide itself regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity.
18
Bizhanova, Aigerim, and Peter Kopp. "The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid." Endocrinology 150, no. 3 (February 5, 2009): 1084–90. http://dx.doi.org/10.1210/en.2008-1437.
Анотація:
Thyroid hormones are essential for normal development and metabolism. Thyroid hormone biosynthesis requires iodide uptake into the thyrocytes and efflux into the follicular lumen, where it is organified on selected tyrosyls of thyroglobulin. Uptake of iodide into the thyrocytes is mediated by an intrinsic membrane glycoprotein, the sodium-iodide symporter (NIS), which actively cotransports two sodium cations per each iodide anion. NIS-mediated transport of iodide is driven by the electrochemical sodium gradient generated by the Na+/K+-ATPase. NIS is expressed in the thyroid, the salivary glands, gastric mucosa, and the lactating mammary gland. TSH and iodide regulate iodide accumulation by modulating NIS activity via transcriptional and posttranscriptional mechanisms. Biallelic mutations in the NIS gene lead to a congenital iodide transport defect, an autosomal recessive condition characterized by hypothyroidism, goiter, low thyroid iodide uptake, and a low saliva/plasma iodide ratio. Pendrin is an anion transporter that is predominantly expressed in the inner ear, the thyroid, and the kidney. Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. In thyroid follicular cells, pendrin is expressed at the apical membrane. Functional in vitro data and the impaired iodide organification observed in patients with Pendred syndrome support a role of pendrin as an apical iodide transporter. This review shows how the sodium-iodide symporter mediates the active transport of iodide at the basolateral membrane of thyrocytes and discusses biallelic mutations in NIS and the effects of pendrin.
19
Dohán, Orsolya, Antonio De la Vieja, Viktoriya Paroder, Claudia Riedel, Mona Artani, Mia Reed, Christopher S. Ginter, and Nancy Carrasco. "The Sodium/Iodide Symporter (NIS): Characterization, Regulation, and Medical Significance." Endocrine Reviews 24, no. 1 (February 1, 2003): 48–77. http://dx.doi.org/10.1210/er.2001-0029.
Анотація:
Abstract The Na+/I− symporter (NIS) is an integral plasma membrane glycoprotein that mediates active I− transport into the thyroid follicular cells, the first step in thyroid hormone biosynthesis. NIS-mediated thyroidal I− transport from the bloodstream to the colloid is a vectorial process made possible by the selective targeting of NIS to the basolateral membrane. NIS also mediates active I− transport in other tissues, including salivary glands, gastric mucosa, and lactating mammary gland, in which it translocates I− into the milk for thyroid hormone biosynthesis by the nursing newborn. NIS provides the basis for the effective diagnostic and therapeutic management of thyroid cancer and its metastases with radioiodide. NIS research has proceeded at an astounding pace after the 1996 isolation of the rat NIS cDNA, comprising the elucidation of NIS secondary structure and topology, biogenesis and posttranslational modifications, transcriptional and posttranscriptional regulation, electrophysiological analysis, isolation of the human NIS cDNA, and determination of the human NIS genomic organization. Clinically related topics include the analysis of congenital I− transport defect-causing NIS mutations and the role of NIS in thyroid cancer. NIS has been transduced into various kinds of cancer cells to render them susceptible to destruction with radioiodide. Most dramatically, the discovery of endogenous NIS expression in more than 80% of human breast cancer samples has raised the possibility that radioiodide may be a valuable novel tool in breast cancer diagnosis and treatment.
20
Schmitz, G., L. Füzesi, J. Struck, U. Siefker, A. Hamann, C. O. Sahlmann, M. Hüfner, and J. Meller. "Expression of the sodium iodide symporter in differentiated thyroid cancer." Nuklearmedizin 44, no. 03 (2005): 86–96. http://dx.doi.org/10.1055/s-0038-1625711.
Анотація:
Summary Aim: Molecular analysis of the expression of the sodium iodide symporter (NIS) in 32 patients with differentiated thyroid cancer (DTC) and correlation with scintigraphic findings (131I,123I) in 19 (59.4%) of them. Patients, methods: NIS expression of 27 primary tumours, 13 lymphnodes and 18 distant metastases was determined by immunostaining using a murine monoclonal anti-NIS-antibody. NIS expression and radionuclide uptake of metastases were analysed by a semiquantitative visual score. Patients were divided into two subgroups: Group 1 (n = 8 patients): indirect correlation of radioiodine uptake (RIU) of subsequent metastases with NIS expression of 7 primary tumours and 3 metastases; Group 2 (n=11 patients): direct correlation of radionuclide uptake with NIS expression of 19 metastases which were excised after imaging. Results: 49 of 58 specimens (84.5%) were NIS-positive. A preserved NIS-expression was found in 12 primary tumours and 8 of 10 (80%) synchrone and 6 of 7 (85.7%) metachrone metastases. Group 1 revealed a 100% positive predictive value (PPV) of a preserved NIS expression in the primary tumour regarding radioiodine uptake in metastases while a lack of NIS expression in the primary tumor did not reliable predict a loss of the metastases’ ability to concentrate radioiodine. In group 2, only 11 of 19 (57.9%) specimens showed a concordant NIS expression and RIU whereas in the remaining 8 cases without visible RIU NIS expression was still present. Conclusions: NIS expression of the primary tumour and metastases in DTC is usually well preserved. We found a positive correlation between NIS expression of the primary and metastatic tissue but could not identify such well correspondence between NIS expression and the RIU of subsequent metastases.
21
Carvalho, Denise P., and Andrea C. F. Ferreira. "The importance of sodium/iodide symporter (NIS) for thyroid cancer management." Arquivos Brasileiros de Endocrinologia & Metabologia 51, no. 5 (July 2007): 672–82. http://dx.doi.org/10.1590/s0004-27302007000500004.
Анотація:
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.
22
De la Vieja, Antonio, Orsolya Dohan, Orlie Levy, and Nancy Carrasco. "Molecular Analysis of the Sodium/Iodide Symporter: Impact on Thyroid and Extrathyroid Pathophysiology." Physiological Reviews 80, no. 3 (July 1, 2000): 1083–105. http://dx.doi.org/10.1152/physrev.2000.80.3.1083.
Анотація:
The Na+/I−symporter (NIS) is an intrinsic membrane protein that mediates the active transport of iodide into the thyroid and other tissues, such as salivary glands, gastric mucosa, and lactating mammary gland. NIS plays key roles in thyroid pathophysiology as the route by which iodide reaches the gland for thyroid hormone biosynthesis and as a means for diagnostic scintigraphic imaging and for radioiodide therapy in hyperthyroidism and thyroid cancer. The molecular characterization of NIS started with the 1996 isolation of a cDNA encoding rat NIS and has since continued at a rapid pace. Anti-NIS antibodies have been prepared and used to study NIS topology and its secondary structure. The biogenesis and posttranslational modifications of NIS have been examined, a thorough electrophysiological analysis of NIS has been conducted, the cDNA encoding human NIS (hNIS) has been isolated, the genomic organization of hNIS has been elucidated, the regulation of NIS by thyrotropin and I− has been analyzed, the regulation of NIS transcription has been studied, spontaneous NIS mutations have been identified as causes of congenital iodide transport defect resulting in hypothyroidism, the roles of NIS in thyroid cancer and thyroid autoimmune disease have been examined, and the expression and regulation of NIS in extrathyroidal tissues have been investigated. In gene therapy experiments, the rat NIS gene has been transduced into various types of human cells, which then exhibited active iodide transport and became susceptible to destruction with radioiodide. The continued molecular analysis of NIS clearly holds the potential of an even greater impact on a wide spectrum of fields, ranging from structure/function of transport proteins to the diagnosis and treatment of cancer, both in the thyroid and beyond.
23
Dohán, Orsolya, Antonio De la Vieja, and Nancy Carrasco. "Hydrocortisone and Purinergic Signaling Stimulate Sodium/Iodide Symporter (NIS)-Mediated Iodide Transport in Breast Cancer Cells." Molecular Endocrinology 20, no. 5 (May 1, 2006): 1121–37. http://dx.doi.org/10.1210/me.2005-0376.
Анотація:
Abstract The sodium/iodide symporter (NIS) mediates a remarkably effective targeted radioiodide therapy in thyroid cancer; this approach is an emerging candidate for treating other cancers that express NIS, whether endogenously or by exogenous gene transfer. Thus far, the only extrathyroidal malignancy known to express functional NIS endogenously is breast cancer. Therapeutic efficacy in thyroid cancer requires that radioiodide uptake be maximized in tumor cells by manipulating well-known regulatory factors of NIS expression in thyroid cells, such as TSH, which stimulates NIS expression via cAMP. Similarly, therapeutic efficacy in breast cancer will likely depend on manipulating NIS regulation in mammary cells, which differs from that in the thyroid. Human breast adenocarcinoma MCF-7 cells modestly express endogenous NIS when treated with all-trans-retinoic acid (tRa). We report here that hydrocortisone and ATP each markedly stimulates tRa-induced NIS protein expression and plasma membrane targeting in MCF-7 cells, leading to at least a 100% increase in iodide uptake. Surprisingly, the adenyl cyclase activator forskolin, which promotes NIS expression in thyroid cells, markedly decreases tRa-induced NIS protein expression in MCF-7 cells. Isobutylmethylxanthine increases tRa-induced NIS expression in MCF-7 cells, probably through a purinergic signaling system independent of isobutylmethylxanthine’s action as a phosphodiesterase inhibitor. We also observed that neither iodide, which at high concentrations down-regulates NIS in the thyroid, nor cAMP has a significant effect on NIS expression in MCF-7 cells. Our findings may open new strategies for breast-selective pharmacological modulation of functional NIS expression, thus improving the feasibility of using radioiodide to effectively treat breast cancer.
24
Matsuda, Akira, and Shinji Kosugi. "A Homozygous Missense Mutation of the Sodium/Iodide Symporter Gene Causing Iodide Transport Defect1." Journal of Clinical Endocrinology & Metabolism 82, no. 12 (December 1, 1997): 3966–71. http://dx.doi.org/10.1210/jcem.82.12.4425.
Анотація:
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.
25
Ferreira, Andrea C. F., Lívia P. Lima, Renata L. Araújo, Glaucia Müller, Renata P. Rocha, Doris Rosenthal, and Denise P. Carvalho. "Rapid regulation of thyroid sodium–iodide symporter activity by thyrotrophin and iodine." Journal of Endocrinology 184, no. 1 (January 2005): 69–76. http://dx.doi.org/10.1677/joe.1.05643.
Анотація:
Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium–iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.
26
Darrouzet, Elisabeth, Fanny Graslin, Didier Marcellin, Iulia Tcheremisinova, Charles Marchetti, Lisa Salleron, Philippe Pognonec, and Thierry Pourcher. "A systematic evaluation of sorting motifs in the sodium–iodide symporter (NIS)." Biochemical Journal 473, no. 7 (March 29, 2016): 919–28. http://dx.doi.org/10.1042/bj20151086.
Анотація:
Human sodium–iodide symporter (NIS) variants were created to suppress predicted binding motifs potentially implicated in trafficking of this protein. A leucine residue in an internal PDZ-binding motif was found to be essential for expression of the symporter at the plasma membrane.
27
Rillema, James A., Ting Xi Yu, and Sissy M. Jhiang. "Effect of prolactin on sodium iodide symporter expression in mouse mammary gland explants." American Journal of Physiology-Endocrinology and Metabolism 279, no. 4 (October 1, 2000): E769—E772. http://dx.doi.org/10.1152/ajpendo.2000.279.4.e769.
Анотація:
Iodide accumulates in milk at a concentration that is more than an order of magnitude higher than the iodide concentration in maternal plasma. In earlier studies from our laboratory, we have shown that prolactin (PRL) enhances iodide accumulation by two- to threefold in cultured mammary tissues taken from pregnant mice. In the present studies, we demonstrate via Western blotting techniques that prolactin elevates the quantity of the sodium iodide symporter (NIS) in cultured mouse mammary tissues. In time-course studies, the onset of the PRL effect of NIS accumulation was found to be between 4 and 16 h after addition of PRL to the explants. The lowest PRL concentration that elicited a significant response was 1 ng/ml, and a maximum effect was elicited with PRL concentrations >100 ng/ml. Actinomycin D, cycloheximide, and thiocyanate abolished the PRL effect on NIS accumulation, whereas perchlorate was without effect. These studies suggest that the PRL stimulation of iodide accumulation in milk is mediated, at least in part, by the PRL stimulation of NIS accumulation in mammary gland tissues. These studies further demonstrate that the PRL effect on NIS accumulation occurs via an RNA protein synthesis-dependent mechanism.
28
Nicola, Juan Pablo, Cécile Basquin, Carla Portulano, Andrea Reyna-Neyra, Monika Paroder, and Nancy Carrasco. "The Na+/I− symporter mediates active iodide uptake in the intestine." American Journal of Physiology-Cell Physiology 296, no. 4 (April 2009): C654—C662. http://dx.doi.org/10.1152/ajpcell.00509.2008.
Анотація:
Absorption of dietary iodide, presumably in the small intestine, is the first step in iodide (I−) utilization. From the bloodstream, I− is actively taken up via the Na+/I− symporter (NIS) in the thyroid for thyroid hormone biosynthesis and in such other tissues as lactating breast, which supplies I− to the newborn in the milk. The molecular basis for intestinal I− absorption is unknown. We sought to determine whether I− is actively accumulated by enterocytes and, if so, whether this process is mediated by NIS and regulated by I− itself. NIS expression was localized exclusively at the apical surface of rat and mouse enterocytes. In vivo intestine-to-blood transport of pertechnetate, a NIS substrate, was sensitive to the NIS inhibitor perchlorate. Brush border membrane vesicles accumulated I− in a sodium-dependent, perchlorate-sensitive manner with kinetic parameters similar to those of thyroid cells. NIS was expressed in intestinal epithelial cell line 6, and I− uptake in these cells was also kinetically similar to that in thyrocytes. I− downregulated NIS protein expression and its own NIS-mediated transport both in vitro and in vivo. We conclude that NIS is functionally expressed on the apical surface of enterocytes, where it mediates active I− accumulation. Therefore, NIS is a significant and possibly central component of the I− absorption system in the small intestine, a system of key importance for thyroid hormone biosynthesis and thus systemic intermediary metabolism.
29
Josefsson, Malin, Lena Evilevitch, Björn Weström, Torsten Grunditz, and Eva Ekblad. "Sodium-Iodide Symporter Mediates Iodide Secretion in Rat Gastric Mucosa In Vitro." Experimental Biology and Medicine 231, no. 3 (March 2006): 277–81. http://dx.doi.org/10.1177/153537020623100306.
Анотація:
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.
30
Liu, Yu-Yu, Xiaoli Zhang, Matthew D. Ringel, and Sissy M. Jhiang. "Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells." Endocrine-Related Cancer 19, no. 3 (February 21, 2012): 291–304. http://dx.doi.org/10.1530/erc-11-0288.
Анотація:
The selective increase of Na+/I−symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I131for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.
31
Vadysirisack, Douangsone D., Anjli Venkateswaran, Zhaoxia Zhang, and Sissy M. Jhiang. "MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner." Endocrine-Related Cancer 14, no. 2 (June 2007): 421–32. http://dx.doi.org/10.1677/erc.1.01263.
Анотація:
The Na+/I− symporter (NIS)-mediated iodide uptake is the basis for targeted radioiodine ablation of thyroid cancers. However, NIS-mediated radioiodide uptake (RAIU) activity is often reduced in thyroid cancers. As mitogen activated protein kinase (MAPK) signaling pathway is activated in about 70% of papillary thyroid carcinoma, we investigated whether MEK (MAPK kinase) inhibition will restore NIS protein levels and NIS-mediated RAIU activity in RET/PTC oncogene-transformed thyroid cells. We found that MEK inhibitor PD98059 increased NIS protein levels within 30 min of treatment. However, the increase of NIS protein level was not accompanied with an increase in NIS-mediated RAIU activity, particularly at early time points of PD98059 treatment. PD98059 also decreased RAIU activity mediated by exogenous NIS in non-thyroid cells. The transient decrease of RAIU activity by PD98059 in thyroid cells was not due to decreased NIS cell surface level, decreased NIS binding affinity for I− , or increased iodide efflux. While PD98059 moderately decreased Na+/K+-ATPase activity, ouabain titration indicates that the extent of decrease in Na+/K+-ATPase activity is much greater than the extent of decrease in RAIU activity. Additionally, a decrease of Na+/K+-ATPase activity was not accompanied with a decrease of biotin uptake activity mediated by Na+-dependent multivitamin transporter. Since PD98059 reduced Vmax− I− without decreasing NIS cell surface levels, it is most likely that PD98059 decreases the turnover rate of iodide transport with an yet to be identified mechanism.
32
Kogai, Takahiko, Yoko Kanamoto, Andrew I. Li, Lisa H. Che, Emi Ohashi, Katsumi Taki, Roshantha A. Chandraratna, Tsukasa Saito, and Gregory A. Brent. "Differential Regulation of Sodium/Iodide Symporter Gene Expression by Nuclear Receptor Ligands in MCF-7 Breast Cancer Cells." Endocrinology 146, no. 7 (July 1, 2005): 3059–69. http://dx.doi.org/10.1210/en.2004-1334.
Анотація:
Abstract 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 β-emitting radioiodide-131 (131I) 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 131I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) β/γ produced marked NIS induction; and selective stimulation of RARα, RARγ, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR β/γ-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 EC50 of tRA for NIS stimulation to approximately 7%, such that 10 −7m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of 131I greater than 10−6m 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 131I after combination treatment.
33
Riesco-Eizaguirre, Garcilaso, and Pilar Santisteban. "A perspective view of sodium iodide symporter research and its clinical implications." European Journal of Endocrinology 155, no. 4 (October 2006): 495–512. http://dx.doi.org/10.1530/eje.1.02257.
Анотація:
The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues, in particular the lactating mammary gland. Cloning and molecular characterization of the NIS have allowed the investigation of its key role in thyroid physiology as well as its potential pathophysiological and therapeutic implications in benign and malignant thyroid diseases. Similarly, elucidating the mechanisms underlying the regulation of NIS in lactating mammary gland and breast cancer, in which more than 80% of cases express endogenous NIS, may lead to findings that have novel implications for pathophysiology and therapy. Two approaches may, in the future, pave the way to extend the use of radioiodide treatment to nonthyroidal cancer. One is based on the reinduction of endogenous NIS expression in thyroid and breast cancer by targeting the main mechanisms involving tumoral transformation and dedifferentiation. The other is based on the application of NIS as a novel cytoreductive gene therapy strategy. NIS offers the unique advantage that it can be used both as a reporter and as a therapeutic gene, so that it is possible to image, monitor, and treat the tumor with radioiodide, just as in differentiated thyroid cancer. This review summarizes the main recent findings in NIS research that have a direct impact on diagnosis and therapeutic management.
34
Kogai, Takahiko, Saima Sajid-Crockett, Lynell S. Newmarch, Yan-Yun Liu, and Gregory A. Brent. "Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells." Journal of Endocrinology 199, no. 2 (September 1, 2008): 243–52. http://dx.doi.org/10.1677/joe-08-0333.
Анотація:
TSH stimulation of sodium iodide symporter (NIS) expression in thyroid cancer promotes radioiodine uptake and is required to deliver an effective treatment dose. Activation of the insulin/phosphoinositide-3-kinase (PI3K) signaling pathway in TSH-stimulated thyroid cells reduces NIS expression at the transcriptional level. We, therefore, investigated the effects of PI3K pathway inhibition on iodide uptake and NIS expression in rat thyroid cell lines and human papillary thyroid cancer cells. A PI3K inhibitor, LY294002, significantly enhanced iodide uptake in two rat thyroid cell lines, FRTL-5 and PCCL3. The induction of Nis mRNA by LY294002 occurred 6 h after treatment, and was abolished by a translation inhibitor, cycloheximide. Expression of the transcription factor, Pax8, which stimulates NIS expression, was significantly increased in PCCL3 cells after LY294002 treatment. Removal of insulin abrogated the stimulatory effects of LY294002 on NIS mRNA and protein expression, but not on iodide uptake. These findings suggest that PI3K pathway inhibition results in post-translational stimulation of NIS. Inhibition of the PI3K pathway also significantly increased iodide uptake (∼3.5-fold) in BHP 2–7 papillary thyroid cancer cells (Ret/PTC1 positive), engineered to constitutively express NIS. Pharmacological inhibition of Akt, a factor stimulated by the PI3K pathway, increased exogenous NIS expression in BHP 2–7 as was seen with LY294002, but not increase the endogenous NIS expression in FRTL-5 cells. PI3K pathway inhibition increases functional NIS expression in rat thyroid cells and some papillary thyroid cancer cells by several mechanisms. PI3K inhibitors have the potential to increase radioiodide accumulation in some differentiated thyroid cancer.
35
Serrano-Nascimento, Caroline, Jamile Calil-Silveira, and Maria Tereza Nunes. "Posttranscriptional regulation of sodium-iodide symporter mRNA expression in the rat thyroid gland by acute iodide administration." American Journal of Physiology-Cell Physiology 298, no. 4 (April 2010): C893—C899. http://dx.doi.org/10.1152/ajpcell.00224.2009.
Анотація:
Iodide is an important regulator of thyroid activity. Its excess elicits the Wolff-Chaikoff effect, characterized by an acute suppression of thyroid hormone synthesis, which has been ascribed to serum TSH reduction or TGF-β increase and production of iodolipids in the thyroid. These alterations take hours/days to occur, contrasting with the promptness of Wolff-Chaikoff effect. We investigated whether acute iodide administration could trigger events that precede those changes, such as reduction of sodium-iodide symporter (NIS) mRNA abundance and adenylation, and if perchlorate treatment could counteract them. Rats subjected or not to methylmercaptoimidazole treatment (0.03%) received NaI (2,000 μg/0.5 ml saline) or saline intraperitoneally and were killed 30 min up to 24 h later. Another set of animals was treated with iodide and perchlorate, in equimolar doses. NIS mRNA content was evaluated by Northern blotting and real-time PCR, and NIS mRNA poly(A) tail length by rapid amplification of cDNA ends–poly(A) test (RACE-PAT). We observed that NIS mRNA abundance and poly(A) tail length were significantly reduced in all periods of iodide treatment. Perchlorate reversed these effects, indicating that iodide was the agent that triggered the modifications observed. Since the poly(A) tail length of mRNAs is directly associated with their stability and translation efficiency, we can assume that the rapid decay of NIS mRNA abundance observed was due to a reduction of its stability, a condition in which its translation could be impaired. Our data show for the first time that iodide regulates NIS mRNA expression at posttranscriptional level, providing a new mechanism by which iodide exerts its autoregulatory effect on thyroid.
36
Spitzweg, C., P. J. Nelson, E. Wagner, P. Bartenstein, W. A. Weber, M. Schwaiger, and J. C. Morris. "The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment." Endocrine-Related Cancer 28, no. 10 (October 1, 2021): T193—T213. http://dx.doi.org/10.1530/erc-21-0177.
Анотація:
Cloning of the sodium iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past two decades, significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery towards promising new applications in disseminated disease, in particular through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination – critically important issues for preclinical development and clinical translation.
37
Beyer, Sasha, Aparna Lakshmanan, Yu-Yu Liu, Xiaoli Zhang, Irene Wapnir, Albert Smolenski, and Sissy Jhiang. "KT5823 Differentially Modulates Sodium Iodide Symporter Expression, Activity, and Glycosylation between Thyroid and Breast Cancer Cells." Endocrinology 152, no. 3 (March 1, 2011): 782–92. http://dx.doi.org/10.1210/en.2010-0782.
Анотація:
Na+/I− symporter (NIS)-mediated iodide uptake into thyroid follicular cells serves as the basis of radioiodine therapy for thyroid cancer. NIS protein is also expressed in the majority of breast tumors, raising potential for radionuclide therapy of breast cancer. KT5823, a staurosporine-related protein kinase inhibitor, has been shown to increase thyroid-stimulating hormone-induced NIS expression, and thus iodide uptake, in thyroid cells. In this study, we found that KT5823 does not increase but decreases iodide uptake within 0.5 h of treatment in trans-retinoic acid and hydrocortisone-treated MCF-7 breast cancer cells. Moreover, KT5823 accumulates hypoglycosylated NIS, and this effect is much more evident in breast cancer cells than thyroid cells. The hypoglycosylated NIS is core glycosylated, has not been processed through the Golgi apparatus, but is capable of trafficking to the cell surface. KT5823 impedes complex NIS glycosylation at a regulatory point similar to brefeldin A along the N-linked glycosylation pathway, rather than targeting a specific N-glycosylated site of NIS. KT5823-mediated effects on NIS activity and glycosylation are also observed in other breast cancer cells as well as human embryonic kidney cells expressing exogenous NIS. Taken together, KT5823 will serve as a valuable pharmacological reagent to uncover mechanisms underlying differential NIS regulation between thyroid and breast cancer cells at multiple levels.
38
Unterholzner, S., M. J. Willhauck, N. Cengic, M. Schütz, B. Göke, J. C. Morris, and C. Spitzweg. "Dexamethasone Stimulation of Retinoic Acid-Induced Sodium Iodide Symporter Expression and Cytotoxicity of 131-I in Breast Cancer Cells." Journal of Clinical Endocrinology & Metabolism 91, no. 1 (January 1, 2006): 69–78. http://dx.doi.org/10.1210/jc.2005-0779.
Анотація:
Abstract Context: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which might offer the potential to treat breast cancer with radioiodine. Objective: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS expression and therapeutic efficacy of 131-I in MCF-7 cells. Design: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern and Western blot analysis after incubation with Dex (10−9 to 10−7m) in the presence of atRA (10−6m) as well as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro clonogenic assay. Results: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of 131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-7 cells treated with Dex in the presence of atRA. Conclusion: Treatment with Dex in the presence of atRA significantly increases functional NIS expression levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7 breast cancer cells.
39
Ajjan, RA, PF Watson, C. Findlay, RA Metcalfe, M. Crisp, M. Ludgate, and AP Weetman. "The sodium iodide symporter gene and its regulation by cytokines found in autoimmunity." Journal of Endocrinology 158, no. 3 (September 1, 1998): 351–58. http://dx.doi.org/10.1677/joe.0.1580351.
Анотація:
Iodide concentration by the thyroid gland, an essential step for thyroid hormone synthesis, is mediated by the Na+/I- symporter (NIS). To identify factors that may regulate this process, we have studied NIS gene expression in the Fisher rat thyroid cell line (FRTL-5) by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) technique. Increasing concentrations of bovine TSH (0.1, 1, 10, 50 and 100 mU/l), with or without tumour necrosis factor-alpha (TNF alpha), interferon-gamma (IFN gamma) or interleukin-1 alpha (IL-1 alpha) were added to FRTL-5 cells previously deprived of TSH for a minimum of 5 days. RNA was extracted and samples were studied for NIS expression. TSH enhanced NIS mRNA expression in a dose-dependent manner, with induction evident at 0.1 mU/l, reaching a peak at 50 mU/l, an effect detected after 6 h of stimulation, but not in the first 2 h. Both TNF alpha and, to a lesser extent, IL-1 alpha inhibited basal and TSH-induced NIS expression. High concentrations of IFN gamma also downregulated TSH-stimulated NIS mRNA expression. Using the same technique, we also investigated NIS mRNA tissue distribution in two male and one female Wistar rats. High levels of NIS expression were detected in the thyroid, stomach, and mammary gland, lower levels were found in the intestine, adipose tissue and liver, borderline levels were expressed in the salivary gland, and no expression was detected in the kidneys. In summary, we have shown that TSH upregulates rat NIS gene expression in vitro, and this induction can be modulated by cytokines. Analysis of the distribution of rat NIS mRNA ex vivo demonstrated variable levels of NIS transcription in different tissue samples.
40
Sodré, Ana Karina M. B., Ileana G. S. Rubio, Ana Luiza R. Galrão, Meyer Knobel, Eduardo K. Tomimori, Venâncio A. F. Alves, Cristina T. Kanamura, et al. "Association of Low Sodium-Iodide Symporter Messenger Ribonucleic Acid Expression in Malignant Thyroid Nodules with Increased Intracellular Protein Staining." Journal of Clinical Endocrinology & Metabolism 93, no. 10 (October 1, 2008): 4141–45. http://dx.doi.org/10.1210/jc.2007-0353.
Анотація:
Context: The expression of sodium iodide symporter (NIS) is required for iodide uptake in thyroid cells. Benign and malignant thyroid tumors have low iodide uptake. However, previous studies by RT-PCR or immunohistochemistry have shown divergent results of NIS expression in these nodules. Objective: The objective of the study was to investigate NIS mRNA transcript levels, compare with NIS and TSH receptor proteins expression, and localize the NIS protein in thyroid nodules samples and their surrounding nonnodular tissues (controls). Design: NIS mRNA levels, quantified by real-time RT-PCR, and NIS and TSH receptor proteins, evaluated by immunohistochemistry, were examined in surgical specimens of 12 benign and 13 malignant nodules and control samples. Results: When compared with controls, 83.3% of the benign and 100% of the malignant nodules had significantly lower NIS gene expression. Conversely, 66.7% of the benign and 100% of malignant nodules had stronger intracellular NIS immunostaining than controls. Low gene expression associated with strong intracellular immunostaining was most frequently detected in malignant (100%) than benign nodules (50%; P = 0.005). NIS protein was located at the basolateral membrane in 24% of the control samples, 8.3% of the benign, and 15.4% of the malignant nodules. The percentage of benign nodules with strong TSH receptor positivity (41.6%) was higher than malignant (7.7%). Conclusion: We confirmed that reduced NIS mRNA expression in thyroid malignant nodules is associated with strong intracellular protein staining and may be related to the inability of the NIS protein to migrate to the cellular basolateral membrane. These results may explain the low iodide uptake of malignant nodules.
41
Rodriguez, Anne-Marie, Barbara Perron, Ludovic Lacroix, Bernard Caillou, Gérard Leblanc, Martin Schlumberger, Jean-Michel Bidart, and Thierry Pourcher. "Identification and Characterization of a Putative Human Iodide Transporter Located at the Apical Membrane of Thyrocytes." Journal of Clinical Endocrinology & Metabolism 87, no. 7 (July 1, 2002): 3500–3503. http://dx.doi.org/10.1210/jcem.87.7.8797.
Анотація:
Iodide transport by thyrocytes is a two step process involving transporters located either in the basal or in the apical membranes of the cell. The sodium iodide symporter (NIS) is localized in the basolateral membrane facing the bloodstream and mediates iodide accumulation into thyrocytes. Pendrin has been proposed as an apical transporter. In order to identify new iodide transporters, we developed a PCR cloning strategy based on NIS sequence homologies. From a human kidney cDNA library, we characterized a gene, located on chromosome 12q23, that encodes a 610 amino acid protein sharing 46% identity (70% similarity) with the human NIS. Functional analysis of the protein expressed in mammalian cells indicates that it catalyzes a passive iodide transport. The protein product was immunohistochemically localized at the apical pole of the thyroid cells facing the colloid lumen. These results suggest that this new identified protein mediates iodide transport from the thyrocyte into the colloid lumen through the apical membrane. It was designated hAIT for human Apical Iodide Transporter.
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Penheiter, Alan R., Troy R. Wegman, Kelly L. Classic, David Dingli, Claire E. Bender, Stephen J. Russell, and Stephanie K. Carlson. "Sodium Iodide Symporter (NIS)-Mediated Radiovirotherapy for Pancreatic Cancer." American Journal of Roentgenology 195, no. 2 (August 2010): 341–49. http://dx.doi.org/10.2214/ajr.09.3672.
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Mitchell, A. M., S. W. Manley, J. C. Morris, K. A. Powell, E. R. Bergert, and R. H. Mortimer. "Sodium Iodide Symporter (NIS) Gene Expression in Human Placenta." Placenta 22, no. 2-3 (February 2001): 256–58. http://dx.doi.org/10.1053/plac.2000.0609.
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Spitzweg, C., I. V. Scholz, E. R. Bergert, D. J. Tindall, C. Y. F. Young, B. Göke, and J. C. Morris. "Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells." Endocrinology 144, no. 8 (August 1, 2003): 3423–32. http://dx.doi.org/10.1210/en.2002-0206.
Анотація:
Abstract We reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of 131I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 −9 to 10−6m) in the presence of 10−9m mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of 131I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10−6m), indicating that it is androgen receptor dependent. The selective killing effect of 131I in NP-1 cells was 50% in NP-1 cells incubated with 10−9m mib. This was increased to 90% in NP-1 cells treated with atRA (10−7m) plus 10−9m mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of 131I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.
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Eleftheriadou, Anna-Maria, Sebastian Mehl, Kostja Renko, Rega H. Kasim, Jasmin-Annabelle Schaefer, Waldemar B. Minich, and Lutz Schomburg. "Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease." European Journal of Endocrinology 183, no. 6 (December 2020): 571–80. http://dx.doi.org/10.1530/eje-20-0566.
Анотація:
Objective Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral sodium-iodide-symporter (NIS (SLC5A5)) and the apical anion exchanger pendrin (PDS (SLC26A4)). Both transmembrane proteins have been described as autoantigens in thyroid disease, yet the reports on autoantibody (aAb) prevalence and diagnostic usefulness are conflicting. Reasons for the inconclusive findings may be small study groups and principle differences in the technologies used. Design We decided to re-evaluate this important issue by establishing novel non-radioactive tests using full-length antigens and comparable protocols, and analyzing a large cohort of thyroid patients (n = 323) and control samples (n = 400). Methods NIS and PDS were recombinantly expressed as fusion protein with firefly luciferase (Luc). Stably transfected HEK293 cells were used as reproducible source of the autoantigens. Results Recombinant NIS-Luc showed iodide transport activity, indicating successful expression and correct processing. Commercial antibodies yielded dose-dependent responses in the newly established assays. Reproducibility of assay signals from patient sera was verified with respect to linearity, stability and absence of matrix effects. Prevalence of PDS-aAb was similar in thyroid patients and controls (7.7% vs 5.0%). NIS-aAb were more prevalent in patients than controls (7.7% vs 1.8%), especially in Graves’ Disease (12.3%). Neither NIS-aAb nor PDS-aAb concentrations were related to TPO-aAb or TSH-receptor-aAb concentrations, or to serum zinc or selenium status. Conclusions Our data highlight a potential relevance of autoimmunity against NIS for thyroid disease, whereas an assessment of PDS-aAb in thyroid patients seems not to be of diagnostic value (yet).
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Popławska-Kita, Anna, Beata Telejko, Katarzyna Siewko, Maria Kościuszko-Zdrodowska, Natalia Wawrusewicz-Kurylonek, Adam Krętowski, Justyna Hryniewicka, et al. "Decreased Expression of Thyroglobulin and Sodium Iodide Symporter Genes in Hashimoto’s Thyroiditis." International Journal of Endocrinology 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/690704.
Анотація:
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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Goel, Apollina, Stephanie K. Carlson, Kelly L. Classic, Suzanne Greiner, Shruthi Naik, Anthony T. Power, John C. Bell та Stephen J. Russell. "Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(Δ51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene". Blood 110, № 7 (1 жовтня 2007): 2342–50. http://dx.doi.org/10.1182/blood-2007-01-065573.
Анотація:
Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(Δ51)-NIS] that has a deletion of methionine 51 in the matrix protein and expresses the human sodium iodide symporter (NIS) gene. VSV(Δ51)-NIS showed specific oncolytic activity against myeloma cell lines and primary myeloma cells and was able to replicate to high titers in myeloma cells in vitro. Iodide uptake assays showed accumulation of radioactive iodide in VSV(Δ51)-NIS–infected myeloma cells that was specific to the function of the NIS transgene. In bg/nd/xid mice with established subcutaneous myeloma tumors, administration of VSV(Δ51)-NIS resulted in high intratumoral virus replication and tumor regression. VSV-associated neurotoxicity was not observed. Intratumoral spread of the infection was monitored noninvasively by serial gamma camera imaging of 123I-iodide biodistribution. Dosimetry calculations based on these images pointed to the feasibility of combination radiovirotherapy with VSV(Δ51)-NIS plus 131I. Immunocompetent mice with syngeneic 5TGM1 myeloma tumors (either subcutaneous or orthotopic) showed significant enhancements of tumor regression and survival when VSV(Δ51)-NIS was combined with 131I. These results show that VSV(Δ51)-NIS is a safe oncolytic agent with significant therapeutic potential in multiple myeloma.
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Perron, B., AM Rodriguez, G. Leblanc, and T. Pourcher. "Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues." Journal of Endocrinology 170, no. 1 (July 1, 2001): 185–96. http://dx.doi.org/10.1677/joe.0.1700185.
Анотація:
Iodide concentration in milk by mammals is a necessary step for thyroid hormone synthesis by the newborn. With the purpose of using the mouse as an animal model to analyse the role of the sodium iodide symporter (NIS) in iodide transport and its regulation in the mammary gland, mouse NIS (mNIS) cDNA was isolated from lactating mice. The cloned sequence shows an open reading frame of 1854 nucleotides encoding a protein of 618 amino acids highly homologous to the rat and human NIS (95% and 81% identity respectively). Expression of mNIS in cultured mammalian cells induced cellular iodide accumulation. This iodide uptake process is sodium dependent and inhibited by thiocyanate and perchlorate. Tissue distribution analysis revealed that mNIS mRNAs are predominantly expressed in thyroid, stomach and in the lactating mammary gland and are present to a lower extent in several other tissues. Our data show for the first time that the level of mNIS mRNA is upregulated in the mammary gland during lactation.
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Henriquez, Tania, Larissa Wirtz, Dan Su, and Heinrich Jung. "Prokaryotic Solute/Sodium Symporters: Versatile Functions and Mechanisms of a Transporter Family." International Journal of Molecular Sciences 22, no. 4 (February 13, 2021): 1880. http://dx.doi.org/10.3390/ijms22041880.
Анотація:
The solute/sodium symporter family (SSS family; TC 2.A.21; SLC5) consists of integral membrane proteins that use an existing sodium gradient to drive the uphill transport of various solutes, such as sugars, amino acids, vitamins, or ions across the membrane. This large family has representatives in all three kingdoms of life. The human sodium/iodide symporter (NIS) and the sodium/glucose transporter (SGLT1) are involved in diseases such as iodide transport defect or glucose-galactose malabsorption. Moreover, the bacterial sodium/proline symporter PutP and the sodium/sialic acid symporter SiaT play important roles in bacteria–host interactions. This review focuses on the physiological significance and structural and functional features of prokaryotic members of the SSS family. Special emphasis will be given to the roles and properties of proteins containing an SSS family domain fused to domains typically found in bacterial sensor kinases.
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Cazarin, Juliana, Corinne Dupuy, and Denise Pires de Carvalho. "Redox Homeostasis in Thyroid Cancer: Implications in Na+/I− Symporter (NIS) Regulation." International Journal of Molecular Sciences 23, no. 11 (May 30, 2022): 6129. http://dx.doi.org/10.3390/ijms23116129.
Анотація:
Radioiodine therapy (RAI) is a standard and effective therapeutic approach for differentiated thyroid cancers (DTCs) based on the unique capacity for iodide uptake and accumulation of the thyroid gland through the Na+/I− symporter (NIS). However, around 5–15% of DTC patients may become refractory to radioiodine, which is associated with a worse prognosis. The loss of RAI avidity due to thyroid cancers is attributed to cell dedifferentiation, resulting in NIS repression by transcriptional and post-transcriptional mechanisms. Targeting the signaling pathways potentially involved in this process to induce de novo iodide uptake in refractory tumors is the rationale of “redifferentiation strategies”. Oxidative stress (OS) results from the imbalance between ROS production and depuration that favors a pro-oxidative environment, resulting from increased ROS production, decreased antioxidant defenses, or both. NIS expression and function are regulated by the cellular redox state in cancer and non-cancer contexts. In addition, OS has been implicated in thyroid tumorigenesis and thyroid cancer cell dedifferentiation. Here, we review the main aspects of redox homeostasis in thyrocytes and discuss potential ROS-dependent mechanisms involved in NIS repression in thyroid cancer.