scholarly journals The Porcine Sodium/Iodide Symporter Gene Exhibits an Uncommon Expression Pattern Related to the Use of Alternative Splice Sites not Present in the Human or Murine Species

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 1074-1085 ◽  
Author(s):  
Samia Selmi-Ruby ◽  
Chantal Watrin ◽  
Severine Trouttet-Masson ◽  
Françoise Bernier-Valentin ◽  
Virginie Flachon ◽  
...  
Keyword(s):  
Alternative Splice ◽  
Sodium Iodide ◽  
Transmembrane Domain ◽  
Splice Variants ◽  
Experimental System ◽  
Splice Sites ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Donor And Acceptor ◽  
Nis Gene

The sodium/iodide symporter (NIS) is a membrane protein mediating the active transport of iodide into the thyroid gland. NIS, expressed by human, rat, and mouse thyrocytes, is encoded by a single transcript. We identified NIS mRNA species of 3.5 and 3 kb in porcine thyrocytes. Because porcine thyrocytes in primary culture is a widely used experimental system for thyroid iodide metabolism, we further examined the origin and the function of the porcine NIS (pNIS) transcripts. We generated a porcine thyroid cDNA library from which four different clones, pNIS-D, F, J, and ΔJ were isolated. pNIS-D encodes a protein of 643 amino acids highly homologous to the human, rat, and mouse NIS. pNIS-F and J differ from each other and from pNIS-D in their C-terminal part. pNIS-ΔJ lacks a six-amino-acid segment within the putative transmembrane domain 10. Transiently expressed in Cos-7 cells, the four pNIS-cDNAs led to the synthesis of proteins targeted at the plasma membrane and conferred perchlorate-sensitive iodide uptake activities to Cos-7 cells, except pNIS-ΔJ, which was devoid of activity. PNIS-D probably derives from the 3.5-kb transcript and pNIS-F, J, and ΔJ from the 3-kb transcript. The relative abundance of pNIS-D, F, and J transcripts in porcine thyrocytes was about 60%, 35%, and 5%, respectively; the ΔJ transcript was not present in detectable amount. By comparing porcine NIS genomic and cDNA sequences, splice donor and acceptor sites accounting for the generation of pNIS-F, J, and ΔJ transcripts were identified. None of the combinations of alternative splice sites found in the pig was present in the human, rat or mouse NIS gene. Our data show that porcine NIS gene, contrary to the NIS gene from other species, gives rise to splice variants leading to three active and one inactive NIS proteins.

scholarly journals Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3423-3432 ◽  
Author(s):  
C. Spitzweg ◽  
I. V. Scholz ◽  
E. R. Bergert ◽  
D. J. Tindall ◽  
C. Y. F. Young ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Prostate Cancer Cells ◽  
Iodide Uptake ◽  
Killing Effect ◽  
Nis Gene

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.

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

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.

scholarly journals Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism

1999 ◽  
pp. 443-457 ◽  
Author(s):  
S Filetti ◽  
JM Bidart ◽  
F Arturi ◽  
B Caillou ◽  
D Russo ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Sodium Iodide ◽  
Human Thyroid ◽  
Thyroid Cell ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Thyroid Carcinomas ◽  
Nis Gene ◽  
Thyroid Cancer Cells

The recent cloning of the gene encoding the sodium/iodide symporter (NIS) has enabled better characterization of the molecular mechanisms underlying iodide transport, thus opening the way to clarifying its role in thyroid diseases. Several studies, at both the mRNA and the protein expression levels, have demonstrated that TSH, the primary regulator of iodide uptake, upregulates NIS gene expression and NIS protein abundance, both in vitro and in vivo. However, other factors, including iodide, retinoic acid, transforming growth factor-beta, interleukin-1alpha and tumour necrosis factor alpha, may participate in the regulation of NIS expression. Investigation of NIS mRNA expression in different thyroid tissues has revealed increased levels of expression in Graves' disease and toxic adenomas, whereas a reduction or loss of NIS transcript was detected in differentiated thyroid carcinomas, despite the expression of other specific thyroid markers. NIS mRNA was also detected in non-thyroid tissues able to concentrate radioiodine, including salivary glands, stomach, thymus and breast. The production of specific antibodies against the NIS has facilitated study of the expression of the symporter protein. Despite of the presence of high levels of human (h)NIS mRNA, normal thyroid glands exhibit a heterogeneous expression of NIS protein, limited to the basolateral membrane of the thyrocytes. By immunohistochemistry, staining of hNIS protein was stronger in Graves' and toxic adenomas and reduced in thyroid carcinomas. Measurement of iodide uptake by thyroid cancer cells is the cornerstone of the follow-up and treatment of patients with thyroid cancer. However, radioiodide uptake is found only in about 67% of patients with persistent or recurrent disease. Several studies have demonstrated a decrease in or a loss of NIS expression in primary human thyroid carcinomas, and immunohistochemical studies have confirmed this considerably decreased expression of the NIS protein in thyroid cancer tissues, suggesting that the low expression of NIS may represent an early abnormality in the pathway of thyroid cell transformation, rather than being a consequence of cancer progression. The relationship between radioiodine uptake and NIS expression by thyroid cancer cells require further study. New strategies, based on manipulation of NIS expression, to obtain NIS gene reactivation or for use as NIS gene therapy in the treatment of radiosensitive cancer, are also being investigated.

scholarly journals Taking Advantage of the TGFB1 Biology in Differentiated Thyroid Cancer to Stimulate Sodium Iodide Symporter (NIS)-Mediated Iodide Uptake in Engineered Mesenchymal Stem Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1033-A1033
Author(s):  
Yang Han ◽  
Viktoria F Koehler ◽  
Nathalie Schwenk ◽  
Kathrin A Schmohl ◽  
Rebekka Spellerberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Nis Gene

Abstract The sodium iodide symporter (NIS) mediates the active transport of iodide into thyroid follicular cells, providing the basis for the use of radioiodide for diagnostic imaging and therapy of differentiated thyroid cancer and also non-thyroidal tumors after tumor-selective NIS gene transfer. Based on their excellent tumor-homing capacity, mesenchymal stem cells (MSCs) can be employed as tumor-selective NIS gene delivery vehicles. Transgenic expression of NIS in genetically engineered MSCs allows noninvasive imaging of functional NIS expression as well as therapeutic application of 131I. The use of promoters activated by tumor micromilieu-derived signals to drive NIS expression enhances selectivity and effectiveness, while limiting potential off-target effects. In this study we aimed to exploit the central role of transforming growth factor B1 (TGFB1) in tumor milieu-associated signaling using a TGFB1-inducible synthetic SMAD-responsive promoter to selectively drive NIS-transgene expression in engineered MSCs (SMAD-NIS-MSC) in the context of differentiated thyroid cancer based on the critical role of TGFB1 in the pathogenesis of radioiodine refractory differentiated thyroid cancer. To evaluate the TGFB1 expression in thyroid cancer cell lines, the TGFB1 concentration in conditioned medium (CM) from an array of established human papillary thyroid cancer (PTC) cell lines (BCPAP and K1) was measured by ELISA. BCPAP-CM showed a higher concentration of TGFB1, while a lower concentration was measured in K1-CM. Stimulation of SMAD-NIS-MSCs with PTC-CM showed a significant increase of NIS-mediated radioiodide-125 uptake in these MSCs in vitro. In addition, iodide uptake in SMAD-NIS-MSCs was significantly stimulated by co-culture with thyroid cancer cells. Cell migration assay was performed to validate the effect of PTC-CM in MSC recruitment. MSCs subjected to a gradient between tumor CM and serum free medium showed a directed chemotaxis towards CM with increased forward migration index (FMI) and center of mass (CoM). In a next step, based on the in vitro studies, SMAD-NIS-MSCs will be systemically applied via the tail vein to mice harboring subcutaneous PTC tumors and tumoral iodide uptake will be monitored by 123I-scintigraphy. Taken together, these data indicate the feasibility of commandeering TGF-β/SMAD signaling in the TGFB1-rich tumor environments of radioiodine refractory differentiated thyroid carcinomas to re-establish functional NIS expression using engineered mesenchymal stem cells as therapy vehicles.

scholarly journals Enhancement of sodium/iodide symporter expression in thyroid and breast cancer

2006 ◽  
Vol 13 (3) ◽  
pp. 797-826 ◽  
Author(s):  
T Kogai ◽  
K Taki ◽  
G A Brent
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Thyroid Cancer ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Wide Range ◽  
Nis Gene ◽  
Tsh Stimulation

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.

scholarly journals Transcriptional Regulation of Human Sodium/Iodide Symporter Gene: A Role for Redox Factor-1

Endocrinology ◽  
2004 ◽  
Vol 145 (3) ◽  
pp. 1290-1293 ◽  
Author(s):  
Cinzia Puppin ◽  
Franco Arturi ◽  
Elisabetta Ferretti ◽  
Diego Russo ◽  
Rosario Sacco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Promoter Activity ◽  
Sodium Iodide ◽  
Independent Effect ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Expression Plasmid ◽  
Thyroid Cells ◽  
Nis Gene

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.

Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake

2016 ◽  
Author(s):  
Alice Fletcher ◽  
Vikki Poole ◽  
Bhavika Modasia ◽  
Waraporn Imruetaicharoenchoke ◽  
Rebecca Thompson ◽  
...  
Keyword(s):  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake

Identification of novel sodium iodide symporter interactors which modulate iodide uptake

2017 ◽  
Author(s):  
Alice Fletcher ◽  
Vikki Poole ◽  
Bhavika Modasia ◽  
Waraporn Imruetaicharoenchoke ◽  
Rebecca Thompson ◽  
...  
Keyword(s):  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake

scholarly journals Rapid regulation of thyroid sodium–iodide symporter activity by thyrotrophin and iodine

2005 ◽  
Vol 184 (1) ◽  
pp. 69-76 ◽  
Author(s):  
Andrea C F Ferreira ◽  
Lívia P Lima ◽  
Renata L Araújo ◽  
Glaucia Müller ◽  
Renata P Rocha ◽  
...  
Keyword(s):  
Sodium Iodide ◽  
Iodine Content ◽  
Concomitant Administration ◽  
High Serum ◽  
Sodium Iodide Symporter ◽  
Physiological Control ◽  
Iodide Uptake ◽  
Thyroid Hormone Biosynthesis ◽  
Serum Tsh

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.

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

2007 ◽  
Vol 51 (5) ◽  
pp. 672-682 ◽  
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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