Search

Background/Objective: Non-metastatic radioactive iodine (RAI) uptake can complicate the interpretation of whole-body scan (WBS) for differentiated thyroid carcinoma (DTC) post-thyroidectomy. We present a patient with DTC whose follow-up WBS showed nonmetastatic multifocal avidity in skeletal tissue, an uncommonly reported site of RAI uptake. Case report: A 42-year-old woman underwent a right hemithyroidectomy, followed by completion thyroidectomy and RAI remnant ablation therapy, for a 4.8 cm thyroid tumor consistent with stage pT3aNxMx follicular thyroid cancer. Follow-up WBS showed intense activity in the thyroid bed, right breast, left medial subcortical acetabulum, and several vertebral bodies. Her biochemical and clinical findings were not suggestive of cancer recurrence. Further workup with SPECT/CT and MRI showed no focal vertebral lesions and identified the left femoral lesion as a benign peripheral nerve sheath. Diagnostic mammography and ultrasound showed no evidence of suspicious breast lesions. Neck ultrasound was clear with no suspicious masses or pathologic lymphadenopathy. She remained in remission on continued active surveillance. Discussion: Nonmetastatic RAI uptake on WBS has many causes, including functional sodium-iodide symporter expression in nonthyroidal tissues, radioiodine accumulation in tissues and bodily fluids, and benign tumors. False-positive uptake can decrease the utility of post-treatment WBS in low-risk patients. Careful clinical examination, biochemical and radiologic follow-up, and close active surveillance can help distinguish false-positive uptake from metastatic or recurrent disease. Conclusion: We describe an uncommon case of RAI uptake in skeletal tissues after thyroidectomy for DTC, and we outline the steps taken to rule out underlying metastases.

Background This study aims to elucidate the associations among dietary seaweed (gim and miyeok/dashima) and iodine intakes, the rs77277498 polymorphism of the SLC5A5 gene codifying the sodium/iodine symporter, and thyroid cancer risk in a Korean population. Methods We conducted a case-control study of 117 thyroid cancer cases and 173 controls who participated in the Cancer Screenee Cohort between 2002 and 2014 at the National Cancer Center, Korea. The amount of seaweed and iodine consumption (g/day) was estimated using the residual energy adjustment method. We calculated odds ratios (ORs) and their 95% confidence intervals (CIs) using a multivariable logistic regression model for the separate and combined effect of dietary iodine-based intake and SLC5A5 polymorphism (rs77277498, C>G) on thyroid cancer. Results Dietary gim and iodine intakes were inversely associated with thyroid cancer, with ORs of 0.50 (95% CI, 0.30 to 0.83) and 0.57 (95% CI, 0.35 to 0.95), respectively, whereas the associations for dietary miyeok/dashima and total seaweed intakes were not significant. However, compared with individuals carrying the C/C genotype of the rs77277498 polymorphism with a low intake of all dietary factors, those carrying the G allele with a high intake had a lower risk of thyroid cancer, with ORs of 0.25 (95% CI, 0.10 to 0.56), 0.31 (95% CI, 0.12 to 0.77), 0.26 (95% CI, 0.10 to 0.62), and 0.30 (95% CI, 0.12 to 0.73) for the consumption of gim, miyeok/dashima, total seaweed, and iodine, respectively. Conclusion In summary, our results supported the evidence of the protective effects of dietary gim and iodine intake against thyroid cancer risk, and this association can be strengthened by SLC5A5 rs77277498 genotypes.

Background: This study aims to elucidate the associations among dietary seaweed (gim and miyeok/dashima) and iodine intakes, the rs77277498 polymorphism of the SLC5A5 gene codifying the sodium/iodine symporter, and thyroid cancer risk in a Korean population. Methods: We conducted a case-control study of 117 thyroid cancer cases and 173 controls who participated in the Cancer Screenee Cohort between 2002 and 2014 at the National Cancer Center, Korea. The amount of seaweed and iodine consumption (g/day) was estimated using the residual energy adjustment method. We calculated odds ratios (ORs) and their 95% confidence intervals (CIs) using a multivariable logistic regression model for the separate and combined effect of dietary iodine-based intake and SLC5A5 polymorphism (rs77277498, C>G) on thyroid cancer. Results: Dietary gim and iodine intakes were inversely associated with thyroid cancer, with ORs of 0.50 (95% CI, 0.30 to 0.83) and 0.57 (95% CI, 0.35 to 0.95), respectively, whereas the associations for dietary miyeok/dashima and total seaweed intakes were not significant. However, compared with individuals carrying the C/C genotype of the rs77277498 polymorphism with a low intake of all dietary factors, those carrying the G allele with a high intake had a lower risk of thyroid cancer, with ORs of 0.25 (95% CI, 0.10 to 0.56), 0.31 (95% CI, 0.12 to 0.77), 0.26 (95% CI, 0.10 to 0.62), and 0.30 (95% CI, 0.12 to 0.73) for the consumption of gim, miyeok/dashima, total seaweed, and iodine, respectively. Conclusion: In summary, our results supported the evidence of the protective effects of dietary gim and iodine intake against thyroid cancer risk, and this association can be strengthened by SLC5A5 rs77277498 genotypes. [ABSTRACT FROM AUTHOR]

Encoding the sodium iodide symporter (NIS) by an adenovirus (Ad) is a promising strategy to facilitate non-invasive imaging and radiotherapy of pancreatic cancer. However, insufficient levels of NIS expression in tumor cells have limited its clinical translation. To optimize Ad-based radiotherapy and imaging, we investigated the effect of Ad death protein (ADP) deletion on NIS expression. We cloned two sets of oncolytic NIS-expressing Ads that differed only in the presence or absence of ADP. We found that ADP expression negatively affected NIS membrane localization and inhibited radiotracer uptake. ADP deletion significantly improved NIS-based imaging in pancreatic cancer models including patient-derived xenografts, where effective imaging was possible for up to 6 weeks after a single virus injection. This study demonstrates that improved oncolysis may hinder the therapeutic effect of oncolytic viruses designed to express NIS. In vivo studies in combination with 131I showed potential for effective radiotherapy. This also highlights the need for further investigation into optimal timing of 131I administration and suggests that repeated doses of 131I should be considered to improve efficacy in clinical trials. We conclude that ADP deletion is essential for effective NIS-based theranostics in cancer.

Iodine is an essential constituent of thyroid hormone. Active iodide accumulation in the thyroid is mediated by the sodium iodide symporter (NIS), comprising the first step in thyroid hormone biosynthesis, which relies on the functional expression of NIS on the cell membrane. The retention of NIS expressed in differentiated thyroid cancer (DTC) cells allows further treatment with post-operative radioactive iodine (RAI) therapy. However, compared with normal thyroid tissue, differentiated thyroid tumors usually show a decrease in the active iodide conveyance and NIS is generally retained within the cells, indicating that posttranslational protein transfer to the plasma membrane is abnormal. In recent years, through in vitro studies and studies of patients with DTC, various methods have been tested to increase the transport rate of NIS to the cell membrane and increase the absorption of iodine. An in-depth understanding of the mechanism of NIS transport to the plasma membrane could lead to improvements in RAI therapy. Therefore, in this review, we discuss the current knowledge concerning the post-translational mechanisms that regulate NIS transport to the cell membrane and the current status of redifferentiation therapy for patients with RAI-refractory (RAIR)-DTC. [ABSTRACT FROM AUTHOR]

Background: Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in THRB, causing resistance to TH (RTH-β). Methods: Clinical, genetic, and biochemical data of the proband's family were collected. Results: The 3-year-old girl was diagnosed with CH due to a homozygous pathogenic c.470del p.(Asn157Thrfs*3) SLC5A5 variant in the neonatal period. She needed a notably high levothyroxine dose to normalize TSH, leading to high free thyroxine levels. There were no signs of hyperthyroidism. Sequencing identified a heterozygous pathogenic c.947G>A p.(Arg316His) THRB variant. Conclusions: To our knowledge, this is the first report of concomitant SLC5A5 and THRB variants causing CH and RTH-β. [ABSTRACT FROM AUTHOR]

Introduction Thyroid iodide transporters, Na+/I– symporter (NIS) and pendrin (PDS), are responsible for supplying this vital micronutrient for thyroid hormone synthesis by thyroid peroxidase (TPO). Both proteins were shown to be expressed, apart from the thyroid, also in other human tissues, including lactating mammary gland. NIS expression in human breast cancers has been widely studied. On the other hand, until now PDS mRNA levels in breast tumor tissue have been estimated only in high throughput analyses. Previously, we have observed that TPO is expressed in normal and cancerous human breast tissues and shows enzymatic activity. However, biochemical activity of TPO in human breast cancer cells requires iodide transport by NIS and PDS. Therefore, to extend our previous study on TPO expression and function in human breast tumors we performed analysis of NIS and PDS levels in the same group of patients. Material and methods The study involved detection of NIS and PDS protein levels by immunohistochemistry and Western blotting, as well as mRNA levels by real-time quantitative polymerase chain reaction. Results Here we provide direct evidence that NIS and PDS are expressed in human breast cancer tissue, with NIS levels being increased and PDS levels decreased in tumor tissue. Interestingly, PDS mRNA levels in breast cancer tissue seem to be influenced by the estrogen receptor status and age of the patients, while NIS mRNA levels were dependent on histological type of the tumor. Conclusions This study provides valuable information important for consideration in diagnostic or therapeutic application of radioiodine in breast cancer management.

Background/objective: Non-metastatic radioactive iodine (RAI) uptake can complicate the interpretation of whole-body scan (WBS) for differentiated thyroid carcinoma (DTC) post-thyroidectomy. We present a patient with DTC whose follow-up WBS showed nonmetastatic multifocal avidity in skeletal tissue, an uncommonly reported site of RAI uptake., Case Report: A 42-year-old woman underwent a right hemithyroidectomy, followed by completion thyroidectomy and RAI remnant ablation therapy, for a 4.8 cm thyroid tumor consistent with stage pT3aNxMx follicular thyroid cancer. Follow-up WBS showed intense activity in the thyroid bed, right breast, left medial subcortical acetabulum, and several vertebral bodies. Her biochemical and clinical findings were not suggestive of cancer recurrence. Further workup with SPECT/CT and MRI showed no focal vertebral lesions and identified the left femoral lesion as a benign peripheral nerve sheath. Diagnostic mammography and ultrasound showed no evidence of suspicious breast lesions. Neck ultrasound was clear with no suspicious masses or pathologic lymphadenopathy. She remained in remission on continued active surveillance., Discussion: Nonmetastatic RAI uptake on WBS has many causes, including functional sodium-iodide symporter expression in nonthyroidal tissues, radioiodine accumulation in tissues and bodily fluids, and benign tumors. False-positive uptake can decrease the utility of post-treatment WBS in low-risk patients. Careful clinical examination, biochemical and radiologic follow-up, and close active surveillance can help distinguish false-positive uptake from metastatic or recurrent disease., Conclusion: We describe an uncommon case of RAI uptake in skeletal tissues after thyroidectomy for DTC, and we outline the steps taken to rule out underlying metastases., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 AACE. Published by Elsevier Inc.)

The sodium-iodide symporter (NIS) mediates the uptake of iodide into the thyroid. Inhibition of NIS function by xenobiotics has been demonstrated to suppress circulating thyroid hormones and perturb related physiological functions. Until recently, few environmental chemicals had been screened for NIS inhibition activity. We previously screened over 1000 chemicals from the ToxCast Phase II (ph1v2 and ph2) libraries using an in vitro radioactive iodide uptake (RAIU) with the hNIS-HEK293T cell line to identify NIS inhibitors. Here, we broaden the chemical space by expanding screening to include the ToxCast e1k library (804 unique chemicals) with initial screening for RAIU at 1 × 10–4 M. Then 209 chemicals demonstrating > 20% RAIU inhibition were further tested in multiple-concentration, parallel RAIU and cell viability assays. This identified 55 chemicals as active, noncytotoxic RAIU inhibitors. Further cytotoxicity-adjusted potency scoring (with NaClO4 having a reference score of 200) revealed five chemicals with moderate to strong RAIU inhibition (scored > 100). These data were combined with our previous PhII screening data to produce binary hit-calls for ~ 1800 unique chemicals (PhII + e1k) with and without cytotoxicity filtering. Results were analyzed with a ToxPrint chemotype-enrichment workflow to identify substructural features significantly enriched in the NIS inhibition hit-call space. We assessed the applicability of enriched PhII chemotypes to prospectively predict NIS inhibition in the e1k dataset. Chemotype enrichments derived for the combined ~ 1800 dataset also identified additional enriched features, as well as chemotypes affiliated with cytotoxicity. These enriched chemotypes provide important new information that can support future data interpretation, structure–activity relationship, chemical use, and regulation. [ABSTRACT FROM AUTHOR]

The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.

Bisphenol A (BPA) is the most common monomer in polycarbonate plastics and an endocrine disruptor. Though some effects of BPA on thyroid hormone (TH) synthesis and action have been described, the impact of this compound on thyroid H2O2 generation remains elusive. H2O2 is a reactive oxygen species (ROS), which could have deleterious effect on thyrocytes if in excess. Therefore, herein we aimed at evaluating the effect of BPA exposition both in vivo and in vitro on H2O2 generation in thyrocytes, besides other essential steps for TH synthesis. Female Wistar rats were treated with vehicle (control) or BPA 40 mg/kg BW for 15 days, by gavage. We then evaluated thyroid iodide uptake, mediated by sodium-iodide symporter (NIS), thyroperoxidase (TPO) and dual oxidase (DOUX) activities (H2O2 generation). Hydrogen peroxide generation was increased, while iodide uptake and TPO activity were reduced by BPA exposition. We have also incubated the rat thyroid cell line PCCL3 with 10−9 M BPA and evaluated Nis and Duox mRNA levels, besides H2O2 generation. Similar to that found in vivo, BPA treatment also led to increased H2O2 generation in PCCL3. Nis mRNA levels were reduced and Duox2 mRNA levels were increased in BPA-exposed cells. To evaluate the importance of oxidative stress on BPA-induced Nis reduction, PCCL3 was treated with BPA in association to N-acetylcysteine, an antioxidant, which reversed the effect of BPA on Nis. Our data suggest that BPA increases ROS production in thyrocytes, what could lead to oxidative damage thus possibly predisposing to thyroid disease.

Radioactive iodine therapy is commonly used as an adjuvant therapy in follicular and papillary thyroid carcinoma (PTC) and in the treatment of Graves’ disease (GD). The basis of this therapy is the accumulation of radioactive iodine by the sodium-iodide symporter (NIS) in the thyroid gland. Expression of NIS by extrathyroidal tissues such as islets of pancreas has been reported. Radioactive iodine uptake by pancreatic beta-cells can potentially damage these cells. In this study, we discuss the possible associations between radioactive iodine and glucose intolerance. Overall, radioactive iodine uptake by the pancreas may damage beta-cells and predispose patients to glucose intolerance or type 2 diabetes, particularly in patients exposed to radioactive iodine therapy following total thyroidectomy. Further studies are needed to clarify and confirm this association.

Abstract In support of the Endocrine Disruptor Screening Program (EDSP), the U.S.EPA's Office of Research and Development (ORD) is developing high-throughput screening (HTS) approaches to identify chemicals that alter target sites in the thyroid hormone (TH) pathway. The sodium iodide symporter (NIS) is a transmembrane glycoprotein that mediates iodide uptake into the thyroid as the initial step of TH biosynthesis. Previously, we screened 293 ToxCast chemicals (ph1v2) using a HEK293T cell line expressing human NIS in parallel radioactive iodide uptake (RAIU) and cell viability assays to identify potential environmental NIS inhibitors. Here, we expanded NIS inhibitor screening for a set of 768 ToxCast Phase II (ph2) chemicals, and applied a novel computational toxicology approach based on the ToxPrint chemotype to identify chemical substructures associated with NIS inhibition. Following single-concentration screening (at 1 × 10−4 M with a 20% inhibition cutoff), 235 samples (228 chemicals) were further tested in multiple-concentration (1 × 10−9 - 1 × 10−4 M) format in both RAIU and cell viability assays. The 167 chemicals that exhibited significant RAIU inhibition were then prioritized using combined RAIU and cell viability responses that were normalized relative to the known NIS inhibitor sodium perchlorate. Some of the highest ranked chemicals, such as PFOS, tributyltin chloride, and triclocarban, have been previously reported to be thyroid disruptors. In addition, several novel chemicals were identified as potent NIS inhibitors. The present results were combined with the previous ph1v2 screening results to produce two sets of binary hit-calls for 1028 unique chemicals, consisting of 273 positives exhibiting significant RAIU inhibition, and 63 positives following application of a cell viability filter. A ToxPrint chemotype-enrichment analysis identified >20 distinct chemical substructural features, represented in >60% of the active chemicals, as significantly enriched in each NIS inhibition hit-call space. A shared set of 9 chemotypes enriched in both hit-call sets indicates stable chemotype signals (insensitive to cytotoxicity filters) that can help guide structure-activity relationship (SAR) investigations and inform future research. Highlights • Xenobiotics can inhibit NIS-mediated I− uptake to disrupt thyroid hormones. • NIS inhibition activity was tested on 768 ToxCast chemicals in tiered RAIU assays. • The 167 RAIU inhibiting chemicals were ranked based on potency and cytotoxicity. • A ToxPrint chemotype-enrichment workflow analyzed test results for 1028 chemicals. • Enriched chemotypes can guide SAR studies for identifying thyroid disruptors. [ABSTRACT FROM AUTHOR]

The tumor-homing properties of mesenchymal stem cells (MSC) have led to their development as delivery vehicles for the targeted delivery of therapeutic genes such as the sodium–iodide symporter (NIS) to solid tumors. External beam radiation therapy may represent an ideal setting for the application of engineered MSC-based gene therapy, as tumor irradiation may enhance MSC recruitment into irradiated tumors through the increased production of select factors linked to MSC migration. In the present study, the irradiation of human liver cancer cells (HuH7; 1–10 Gy) showed a strong dose-dependent increase in steady-state mRNA levels of CXCL8, CXCL12, FGF2, PDGFB, TGFB1, THBS1, and VEGF (0–48 h), which was verified for most factors at the protein level (after 48 h). Radiation effects on directed MSC migration were tested in vitro using a live cell tracking migration assay and supernatants from control and irradiated HuH7 cells. A robust increase in mean forward migration index, mean center of mass, and mean directionality of MSCs toward supernatants was seen from irradiated as compared to non-irradiated tumor cells. Transferability of this effect to other tumor sources was demonstrated using the human breast adenocarcinoma cell line (MDA-MB-231), which showed a similar behavior to radiation as seen with HuH7 cells in quantitative polymerase chain reaction and migration assay. To evaluate this in a more physiologic in vivo setting, subcutaneously growing HuH7 xenograft tumors were irradiated with 0, 2, or 5 Gy followed by CMV-NIS-MSC application 24 h later. Tumoral iodide uptake was monitored using 123I-scintigraphy. The results showed increased tumor-specific dose-dependent accumulation of radioiodide in irradiated tumors. The results demonstrate that external beam radiation therapy enhances the migratory capacity of MSCs and may thus increase the therapeutic efficacy of MSC-mediated NIS radionuclide therapy. [ABSTRACT FROM AUTHOR]

The silencing of thyroid-related genes presents difficulties in radioiodine therapy for anaplastic thyroid cancers (ATCs). Tunicamycin (TM), an N-linked glycosylation inhibitor, is an anticancer drug. Herein, we investigated TM-induced restoration of responsiveness to radioiodine therapy in radioiodine refractory ATCs. 125I uptake increased in TM-treated ATC cell lines, including BHT101 and CAL62, which was inhibited by KClO4, a sodium-iodide symporter (NIS) inhibitor. TM upregulated the mRNA expression of iodide-handling genes and the protein expression of NIS. TM blocked pERK1/2 phosphorylation in both cell lines, but AKT (protein kinase B) phosphorylation was only observed in CAL62 cells. The downregulation of glucose transporter 1 protein was confirmed in TM-treated cells, with a significant reduction in 18F-fluorodeoxyglucose (FDG) uptake. A significant reduction in colony-forming ability and marked tumor growth inhibition were observed in the combination group. TM was revealed to possess a novel function as a redifferentiation inducer in ATC as it induces the restoration of iodide-handling gene expression and radioiodine avidity, thereby facilitating effective radioiodine therapy.

The clue function of thyroid follicular cells is iodide (I) uptake and thyroid hormones production. NIS mediates the active transport of I into the thyroid follicular cells. It is impossible to perform effective 131I radioablation (131I RA) up to 10% of all differentiated thyroid cancer (DTC) owing to dedifferentiation and lost ability to cumulate I. To distinguish this group of patient preoperatively is difficult. Aim. To assess the utility of using membrane located NIS detection as marker of unfavorable prognosis for DTC after 131I RA. Materials and methods. We enrolled in our study retrospectively sixty patients with DTC operated from 2005 to 2008. Based on postop routine histology examination we performed TNM staging. Forty-five patients received 131I RA postoperatively. During 60 month of follow up recurrence were detected in 20 cases. In all 60 patients' level of membrane located NIS expression were detected immunohistochemicaly (IHC) in primary thyroid tumor. All statistical analysis performed using PC program Statistica 7.0. Results. We found that mean level of membrane located NIS expression in DTC is 4.5%, with maximum up to 10%, whereas mean level of NIS expression in normal tissue is 30—40%. Least mean level of NIS expression was in patients group with recurrence of DTC after 131I RA (p=0.00083). We proved that crutial for recurrence of DTC after 131I RA were decreased level of membrane located NIS expression less than 1%. As well as we found statistically significant correlation between Recurrence Free Survival (RFS) and level of NIS expression (p 0.005). Conclusion. Membrane location of NIS determines its functional activity, and membrane located NIS amount decreases in DTC. Detection of membrane located NIS in DTC has prognostic value.

Summary: Na+/I− symporter (NIS) transports iodide into thyrocytes, a fundamental step for thyroid hormone biosynthesis. Our aim was to evaluate NIS regulation in different status of goitrogenesis and its underlying mechanisms. Wistar rats were treated with methimazole (MMI) for 5 and 21 days, to achieve different status of goiter. We then evaluated the effect of MMI removal for 1 day (R1d), after 5 (R1d‐5d) or 21 (R1d‐21d) days of MMI treatment. MMI increased thyroid weight, iodide uptake and in vitro TPO activity in a time‐dependent way. Although MMI removal evoked a rapid normalization of TPO activity in R1d‐5d, it was still high in R1d‐21d. On the other hand, iodide uptake was rapidly down‐regulated in R1d‐21d, but not in R1d‐5d, suggesting that the increased TPO activity in R1d‐21d led to increased intraglandular organified iodine (I‐X), which is known to inhibit iodide uptake. Since TGFβ has been shown to mediate some effects of I‐X, we evaluated TGFβ and TGFβ receptor mRNA levels, which were increased in R1d‐21d. Moreover, it has been demonstrated that TGFβ stimulates NOX4. Accordingly, our data revealed increased NOX4 expression and H2O2 generation in R1d‐21d. Finally, we evaluated the effect of H2O2 on NIS function and mRNA levels in PCCL3 thyroid cell line, which were reduced. Thus, the present study suggests that there is a relationship between the size of the goiter and NIS regulation and that the mechanism might involve I‐X, TGFβ, NOX4 and increased ROS production. [ABSTRACT FROM AUTHOR]

Iodide uptake across the membranes of thyroid follicular cells and cancer cells occurs through an active transport process mediated by the sodium-iodide symporter (NIS). The rat and human NIS-coding genes were cloned and identified in 1996. Evaluation of NIS gene and protein expression is critical for the management of thyroid cancer, and several approaches to increase NIS levels have been tried. Identification of the NIS gene has provided a means of expanding its role in radionuclide therapy and molecular target-specific theragnosis (therapy and diagnosis using the same molecular target). In this article, we describe the relationship between NIS expression and the thyroid carcinoma treatment using I-131 and alternative therapeutic approaches.

Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of the thyroid-specific expression of the human sodium iodide symporter (hNIS). Here, we explore the efficacy of a novel form of gene therapy using prostate-specific membrane antigen (PSMA) promoter-mediated hNIS gene transfer followed by radioiodine administration for the treatment of castration-resistant prostate cancer (CRPC). The androgen-dependent C33 LNCaP cell line and the androgen-independent C81 LNCaP cell line were transfected by adenovirus. PSMA promoter-hNIS (Ad.PSMApro-hNIS) or adenovirus.cytomegalovirus-hNIS containing the cytomegalovirus promoter (Ad.CMV-hNIS) or a control virus. The iodide uptake was measured in vitro. The in vivo iodide uptake by C81 cell xenografts in nude mice injected with an adenovirus carrying the hNIS gene linked to PSMA and the corresponding tumor volume fluctuation were assessed. Iodide accumulation was shown in different LNCaP cell lines after Ad.PSMApro-hNIS and Ad.CMV-hNIS infection, but not in different LNCaP cell lines after adenovirus.cytomegalovirus (Ad.CMV) infection. At each time point, higher iodide uptake was shown in the C81 cells infected with Ad.PSMApro-hNIS than in the C33 cells (P < 0.05). An in vivo animal model showed a significant difference in 131 I radioiodine uptake in the tumors infected with Ad.PSMApro-hNIS, Ad.CMV-hNIS and control virus (P < 0.05) and a maximum reduction of tumor volume in mice infected with Ad.PSMApro-hNIS. These results show prostate-specific expression of the hNIS gene delivered by the PSMA promoter and effective radioiodine therapy of CRPC by the PSMA promoter-driven hNIS transfection.

Radioactive iodine therapy is commonly used as an adjuvant therapy in follicular and papillary thyroid carcinoma (PTC) and in the treatment of Graves' disease (GD). The basis of this therapy is the accumulation of radioactive iodine by the sodium-iodide symporter (NIS) in the thyroid gland. Expression of NIS by extrathyroidal tissues such as islets of pancreas has been reported. Radioactive iodine uptake by pancreatic beta-cells can potentially damage these cells. In this study, we discuss the possible associations between radioactive iodine and glucose intolerance. Overall, radioactive iodine uptake by the pancreas may damage beta-cells and predispose patients to glucose intolerance or type 2 diabetes, particularly in patients exposed to radioactive iodine therapy following total thyroidectomy. Further studies are needed to clarify and confirm this association. [ABSTRACT FROM AUTHOR]

Purpose: Thyroid concentrates radioactive iodine by sodium-iodide symporter; this is used for treating hyperthyroidism and thyroid cancer. Pancreas expresses NIS and radioactive iodine uptake may damage pancreatic beta-cells and predispose patients to type 2 diabetes. The aim of this study was to determine whether radioactive iodine is associated with glucose metabolism in thyroidectomized rats. Methods: Forty male Wistar rats were divided into four groups ( n = 10/each); control, thyroidectomized, thyroidectomized-treated with 131-I (TX+I), and thyroidectomized-treated with 131-I and l-thyroxine (TX+I+T). At the end of study, serum fasting glucose, insulin, thyroid-stimulating hormone, and free tetraiodothyronine were measured, intraperitoneal glucose tolerance test was performed, and homeostasis model assessment-insulin resistance was calculated. In in vitro experiments, glucose-stimulated insulin secretion from pancreatic islets and sodium-iodide symporter mRNA expression in thyroid and islets were determined. Results: Compared to control group, free tetraiodothyronine was lower by 41 and 77% and thyroid-stimulating hormone was higher by 36 and 126% in thyroidectomized and TX+I groups, respectively. Compared to controls, rats in TX+I group had glucose intolerance as assessed using the area under curve of intraperitoneal glucose tolerance test (12,376 ± 542 vs. 20,769 ± 1070, P < 0.001) and l-thyroxine replacement therapy restored the value (14,286 ± 328.24) to near normal. Fasting insulin and homeostasis model assessment-insulin resistance were comparable in all groups, however fasting glucose was higher in TX+I group. In in vitro experiments, glucose-stimulated insulin secretion from islets did not differ between groups. Conclusion: Radioactive iodine therapy per se had no effect on glucose metabolism, just intensified thyroid hormone deficiency and the alterations on glucose metabolism in thyroidectomized rats. l-thyroxine therapy restored the glucose intolerance observed in radioactive iodine-treated thyroidectomized rats. [ABSTRACT FROM AUTHOR]

Perchlorate is a ubiquitous environmental contaminant that has widespread endocrine disrupting effects in vertebrates, including threespine stickleback ( Gasterosteus aculeatus ). The target of perchlorate is thyroid tissue where it induces changes in the organization, activation, and morphology of thyroid follicles and surrounding tissues. To test the hypothesis that some phenotypes of perchlorate toxicity are not mediated by thyroid hormone, we chronically exposed stickleback beginning at fertilization to perchlorate (10, 30, 100 ppm) or control water with and without supplementation of either iodide or thyroxine (T 4 ). Stickleback were sampled across a one-year timespan to identify potential differences in responses to treatment combinations before and after sexual maturation. We found that most thyroid histomorphological phenotypes induced by perchlorate (follicle proliferation, reduced follicle area (adults only), colloid depletion, thyrocyte hypertrophy (subadults only)) were significantly ameliorated by exogenous iodide supplementation. In contrast, treatment with exogenous T 4 did not correct any of the thyroid-specific histopathologies induced by perchlorate. Whole-body thyroid hormone concentrations were not significantly affected by perchlorate exposure; however, supplementation with iodide and T 4 significantly increased T 4 concentrations. This study also revealed an increased erythrocyte area in the thyroid region of perchlorate-exposed adults, while lipid droplet number increased in perchlorate-exposed subadults. Increased erythrocyte area was ameliorated by both iodide and T 4 , while neither supplement was able to correct lipid droplet number. Our finding on lipid droplets indicates that exposure to perchlorate in early development may have obesogenic effects. [ABSTRACT FROM AUTHOR]

Background: Major regulation of thyroid gland function is mediated by thyrotropin (TSH) activating the TSH receptor (TSHR) and inducing upregulation of genes involved in thyroid hormone synthesis. Evidence suggests that the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) may play a role in regulating TSHR functional effects. This study examined the potential role of TSHR/IGF-1R crosstalk in primary cultures of human thyrocytes. Results: TSH/IGF-1 co-treatment elicited additive effects on thyroglobulin ( TG), thyroperoxidase ( TPO), and deiodinase type 2 ( DIO2) mRNA levels but synergistic effects on sodium-iodide symporter ( NIS) mRNA. Similar cooperativity was seen on the level of TG protein secretion (additive) and NIS protein expression (synergistic). The IGF-1R tyrosine kinase inhibitor linsitinib inhibited TSH-stimulated upregulation of NIS but not TG, indicating that NIS regulation is in part IGF-1R dependent and occurs via receptor crosstalk. Cooperativity was not seen at the level of cAMP/protein kinase A (PKA) signaling, IGF-1R phosphorylation, or Akt activation. However, TSH and IGF-1 synergistically activated ERK1/2. Pharmacological inhibition of ERK1/2 by the MEK1/2 inhibitor U0126 and of Akt by MK-2206 virtually abolished NIS stimulation by TSH and the synergistic effect of IGF-1. Conclusion: As linsitinib inhibited upregulation of NIS stimulated by TSH alone, it is concluded that crosstalk between TSHR and IGF-1R, without agonist activation of IGF-1R, plays a role in NIS regulation in human thyrocytes via a mechanism involving ERK1/2 and/or Akt. Fully understanding the nature of this crosstalk has clinical implications for the treatment of thyroid diseases, including thyroid cancer. [ABSTRACT FROM AUTHOR]