Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH

Abstract The transcriptional regulation of the human sodium/iodide symporter (NIS) gene in normal and transformed thyroid cells is a crucial issue in attempting to restore iodide uptake and use radioiodine as a therapeutic treatment of thyroid cancer. Previous investigations have shown that the multifunctional protein apurinic apyrimidinic endonuclease/redox factor 1 (APE/Ref-1) plays an important role in regulation of thyroid-specific gene transcription. In this study, we investigated the effects of APE/Ref-1 on human NIS promoter activity. Cotransfection experiments performed in nonthyroid HeLa cells demonstrated that APE/Ref-1 exerts both PAX8-dependent and PAX8-independent effects. In fact, in the absence of PAX8, overexpression of APE/Ref-1 enhanced NIS promoter activity 2-fold. When the expression plasmid of APE/Ref-1 was transfected together with an expression plasmid for PAX8, a strong cooperative effect was detected with an increase of NIS promoter activity 9-fold over control. The PAX8-independent effect of APE/Ref-1 was specific for the NIS promoter, resulting not present for the promoter of the thyroperoxidase (TPO) gene. It was, at least in part, due to the up-regulation of the transcriptional activity of the ubiquitous factor early growth response-1 (Egr-1). In the thyroid tumor cell lines TPC-1 and B-CPAP, APE/Ref-1 was not effective by itself, and it also failed to increase PAX8 stimulation on NIS promoter activity. These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. However, restoring the PAX8-APE/Ref-1 expression in tumor cells may not be sufficient to obtain adequate levels of NIS gene expression.

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Effect of Iodide on Human Choriogonadotropin, Sodium-Iodide Symporter Expression, and Iodide Uptake in BeWo Choriocarcinoma Cells

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2358 ◽

2007 ◽

Vol 92 (10) ◽

pp. 4046-4051 ◽

Cited By ~ 17

Author(s):

Huika Li ◽

Kerry Richard ◽

Brett McKinnon ◽

Robin H. Mortimer

Keyword(s):

Gene Expression ◽

Protein Expression ◽

Mrna Expression ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Hormone Synthesis ◽

Human Choriogonadotropin ◽

Fetal Thyroid ◽

Choriocarcinoma Cells

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.

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Retinoic Acid Increases Sodium/Iodide Symporter mRNA Levels in Human Thyroid Cancer Cell Lines and Suppresses Expression of Functional Symporter in Nontransformed FRTL-5 Rat Thyroid Cells

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1997.7715 ◽

1997 ◽

Vol 240 (3) ◽

pp. 832-838 ◽

Cited By ~ 115

Author(s):

C. Schmutzler ◽

R. Winzer ◽

J. Meissner-Weigl ◽

J. Köhrle

Keyword(s):

Thyroid Cancer ◽

Retinoic Acid ◽

Sodium Iodide ◽

Human Thyroid ◽

Mrna Levels ◽

Thyroid Cancer Cell ◽

Sodium Iodide Symporter ◽

Thyroid Cells ◽

Thyroid Cancer Cell Lines ◽

Rat Thyroid

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Iodide symporter gene expression in normal and transformed rat thyroid cells

Acta Endocrinologica ◽

10.1530/eje.0.1400447 ◽

1999 ◽

pp. 447-451 ◽

Cited By ~ 42

Author(s):

F Trapasso ◽

R Iuliano ◽

E Chiefari ◽

F Arturi ◽

A Stella ◽

...

Keyword(s):

Gene Expression ◽

Cell Lines ◽

Inhibitory Effect ◽

Mrna Levels ◽

Iodide Uptake ◽

Thyroid Cells ◽

Transformed Cell ◽

Nis Gene ◽

Rat Thyroid ◽

Transformed Cell Lines

OBJECTIVE: Decrease or loss of the Na+/I- symporter (NIS) activity profoundly affects the suitability of the use of radioiodine to detect or treat metastatic thyroid tissues. The aim of our study was to verify whether specific oncogene abnormalities were responsible for the alteration in NIS activity in thyroid cells. DESIGN AND METHODS: Expression of the NIS gene was investigated by Northern blot analysis in normal and in some oncogene-transformed cell lines with different degrees of malignancy which had lost the iodide uptake ability. RESULTS: NIS gene expression was up-regulated by TSH in a dose-dependent and time-dependent way in normal PC Cl 3 cells. The same effect was observed by activating the cAMP-dependent pathway by forskolin. Conversely, insulin and 12-O-tetradecanoylphorbol-13-acetate (TPA) showed a partial inhibitory effect on NIS gene expression. The oncogene-transformed cell lines PC v-erbA, PC HaMSV, PC v-raf, and PC E1A cells showed reduced NIS mRNA levels compared with the normal PC Cl 3 cells. Conversely, an almost complete absence of NIS gene expression was found in PC RET/PTC, PC KiMSV, PC p53(143ala), and PC PyMLV cell lines. CONCLUSIONS: Our data show that oncogene activation could play a role in affecting the iodide uptake ability in thyroid tumoral cells; different mechanisms are involved in the oncogene-dependent loss of NIS activity in transformed thyroid cells.

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Iodide excess regulates its own efflux: a possible involvement of pendrin

AJP Cell Physiology ◽

10.1152/ajpcell.00210.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. C576-C582 ◽

Cited By ~ 12

Author(s):

Jamile Calil-Silveira ◽

Caroline Serrano-Nascimento ◽

Peter Andreas Kopp ◽

Maria Tereza Nunes

Keyword(s):

Plasma Membrane ◽

Thyroid Hormone ◽

Thyroid Hormones ◽

Sodium Iodide ◽

Inhibitory Effect ◽

Membrane Insertion ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Hormone Synthesis ◽

Rat Thyroid

Adequate iodide supply and metabolism are essential for thyroid hormones synthesis. In thyrocytes, iodide uptake is mediated by the sodium-iodide symporter, but several proteins appear to be involved in iodide efflux. Previous studies demonstrated that pendrin is able to mediate apical efflux of iodide in thyrocytes. Acute iodide excess transiently impairs thyroid hormone synthesis, a phenomenon known as the Wolff-Chaikoff effect. Although the escape from this inhibitory effect is not completely understood, it has been related to the inhibition of sodium-iodide symporter-mediated iodide uptake. However, the effects of iodide excess on iodide efflux have not been characterized. Herein, we investigated the consequences of iodide excess on pendrin abundance, subcellular localization, and iodide efflux in rat thyroid PCCl3 cells. Our results indicate that iodide excess increases pendrin abundance and plasma membrane insertion after 24 h of treatment. Moreover, iodide excess increases pendrin half-life. Finally, iodide exposure also increases iodide efflux from PCCl3 cells. In conclusion, these data suggest that pendrin may have an important role in mediating iodide efflux in thyrocytes, especially under conditions of iodide excess.

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Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression

Journal of Endocrinology ◽

10.1677/joe.0.1670125 ◽

2000 ◽

Vol 167 (1) ◽

pp. 125-135 ◽

Cited By ~ 50

Author(s):

T Kogai ◽

F Curcio ◽

S Hyman ◽

EM Cornford ◽

GA Brent ◽

...

Keyword(s):

Messenger Rna ◽

Sodium Iodide ◽

Human Thyroid ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Thyroid Cells ◽

Protein Levels ◽

Normal Human ◽

Tsh Stimulation ◽

Stimulation Of

Iodide uptake by the sodium/iodide symporter (NIS) in thyrocytes is essential for thyroid hormone production. Reduced NIS activity has been reported in thyroid diseases, including thyroid cancer and congenital hypothyroidism. The study of iodide uptake in thyrocytes has been limited by the availability of appropriate in vitro models. A new culture technique was recently developed that allows normal human thyroid primary culture cells to grow as monolayer cells and express differentiated functions for more than 3 months. We used this technique to study the effect of follicle formation and TSH on iodide uptake in these cells. Iodide uptake by the cells grown in monolayer was very low. Follicle formation was induced from monolayer cells, and electron micrographs demonstrated cell polarity in the follicles. No significant increase in iodide uptake was observed after TSH treatment of cells in monolayer or when follicle formation was induced without TSH. TSH stimulation of follicles, however, significantly increased iodide uptake ( approximately 4. 4-fold; P<0.001). Compared with iodide uptake in monolayers, the combination of follicle formation and TSH treatment stimulated iodide uptake synergistically to 12.0-fold (P<0.001). NIS messenger RNA (mRNA) and protein levels were almost the same in both monolayer cells and follicles. TSH treatment of monolayers and follicles produced significant (P<0.05) stimulation of mRNA ( approximately 4. 8- and approximately 4.3-fold respectively) and protein ( approximately 6.8- and 4.9-fold respectively). TSH stimulated NIS protein levels in both monolayer and follicles, however, stimulation of functional iodide uptake was only seen with TSH stimulation of follicles. The function of NIS may involve post-transcriptional events, such as intracellular sorting, membrane localization of NIS or another NIS regulatory factor. Polarized functions, such as iodide efflux into follicular lumina, may also contribute to the increased iodide concentration after follicle formation.

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Induction of Thyroid Gene Expression and Radioiodine Uptake in Thyroid Cancer Cells by Targeting Major Signaling Pathways

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1888 ◽

2010 ◽

Vol 95 (2) ◽

pp. 820-828 ◽

Cited By ~ 62

Author(s):

Peng Hou ◽

Ermal Bojdani ◽

Mingzhao Xing

Keyword(s):

Gene Expression ◽

Thyroid Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Histone Deacetylase ◽

Sodium Iodide ◽

Therapeutic Potential ◽

Sodium Iodide Symporter ◽

Thyroid Cells ◽

Thyroid Cancer Cells

Abstract Context: Radioiodine ablation is commonly used to treat thyroid cancer, but a major challenge is often the loss of radioiodine avidity of the cancer caused by aberrant silencing of iodide-handling genes. Objectives: This study was conducted to test the therapeutic potential of targeting the aberrantly activated MAPK and PI3K/Akt/mTOR pathways and histone deacetylase to restore radioiodine avidity in thyroid cancer cells. Experimental Design: We tested the effects of specific inhibitors targeting these pathways/molecules that had established clinical applicability, including the MAPK kinase inhibitor RDEA119, mTOR inhibitor temsirolimus, Akt inhibitor perifosine, and histone deacetylase inhibitor SAHA, individually or in combinations, on the expression of iodide-handling genes and radioiodide uptake in a large panel of thyroid cancer cell lines. Results: The expression of a large number of iodide-handling genes could be restored, particularly the sodium/iodide symporter, TSH receptor, and thyroperoxidase, by treating cells with these inhibitors. The effect was particularly robust and synergistic when combinations of inhibitors containing SAHA were used. Robust expression of sodium/iodide symporter in the cell membrane, which plays the most important role in iodide uptake in thyroid cells, was confirmed by immunofluorescent microscopy. Radioiodide uptake by cells was correspondingly induced under these conditions. Thyroid gene expression and radioiodide uptake could both be further enhanced by TSH. Conclusions: Targeting major signaling pathways could restore thyroid gene expression and radioiodide uptake in thyroid cancer cells. Further studies are warranted to test this therapeutic potential in restoring radioiodine avidity of thyroid cancer cells for effective ablation treatment.

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