Curcumin enhances the membrane trafficking of sodium iodide symporter and augments radioiodine uptake in dedifferentiated thyroid cancer cells via suppression of PI3K-AKT signaling pathway

Normal thyrocytes and thyroid cancer cells are characterized by possession of a sodium iodide symporter. Radioiodine administration is a unique and powerful means of treating differentiated thyroid cancer because of the ability of thyroid cancer cells to concentrate beta-emitting radiolabeled iodine. Several manipulations, such as iodine depletion and thyroid hormone-stimulating hormone elevation, are used to enhance uptake of radiolabeled iodine by tumor cells. Adjuvant radioiodine therapy, given to patients without evidence of residual disease, enhances the sensitivity of subsequent surveillance and may decrease recurrence rates and mortality. However, its exact role in the management of low-risk patients merits further investigation. In contrast, radioactive iodine therapy used in patients with residual or metastatic disease clearly improves outcomes. Several studies show decreased recurrence and mortality rates in patients treated with radioiodine compared with those not receiving radioactive iodine. Adverse events from radioiodine therapy include salivary gland dysfunction, bone marrow suppression, and reproductive disturbances. Side effects of radioiodine therapy are generally greater when higher activities of radioiodine are used and may be transient or permanent. Secondary malignancies also may occur after radioiodine therapy. These side effects must be weighed against potential benefits, especially when radioactive iodine is used as adjuvant therapy. Stimulation of the expression of the sodium iodide symporter, or its introduction de novo into nonthyroid cells, is promising in treating poorly differentiated thyroid cancer and nonthyroid malignancies, respectively.

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Downregulation of miR-146b-3p Inhibits Proliferation and Migration and Modulates the Expression and Location of Sodium/Iodide Symporter in Dedifferentiated Thyroid Cancer by Potentially Targeting MUC20

Frontiers in Oncology ◽

10.3389/fonc.2020.566365 ◽

2021 ◽

Vol 10 ◽

Author(s):

Shasha Hou ◽

Xiaorui Xie ◽

Jing Zhao ◽

Cailan Wu ◽

Ning Li ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Radioactive Iodine ◽

Sodium Iodide Symporter ◽

Whole Exome ◽

And Migration ◽

Thyroid Cancer Cells ◽

Proliferation And Migration

The dedifferentiation of differentiated thyroid cancer (DTC) is a challenging problem for radioactive iodine (131I) treatment, also known as radioiodine refractory differentiated thyroid cancer (RAIR-DTC). The purpose of this study was to further explore the mechanism of the redifferentiation of dedifferentiated thyroid cancer. Ineffective and effective groups of 131I therapy were analyzed and compared in both our clinical and TCGA samples. Whole-exome sequencing, mutation analysis, transcriptome analysis, and in vitro functional experiments were conducted. FLG, FRG1, MUC6, MUC20, and PRUNE2 were overlapping mutation genes between our clinical cases, and the TCGA cases only appeared in the ineffective group. The expression of miR-146b-3p target MUC20 was explored. The expression levels of miR-146b-3p and MUC20 were significantly increased, and the inhibition of miR-146b-3p expression significantly inhibited proliferation and migration, promoted apoptosis, regulated the expression and location of thyroid differentiation-related genes, and sodium/iodide symporter (NIS) in dedifferentiated thyroid cancer cells (WRO). Thus, miR-146b-3p potentially targets MUC20 participation in the formation of DTC dedifferentiation, resulting in resistance to 131I and the loss of the iodine uptake ability of DTC cancer foci, promoting refractory differentiated thyroid cancer. miR-146b-3p may be a potentially therapeutic target for the reapplication of 131I therapy in dedifferentiated thyroid cancer patients.

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Synergistic inhibition of MEK/ERK and BRAF V600E with PD98059 and PLX4032 induces sodium/iodide symporter (NIS) expression and radioiodine uptake in BRAF mutated papillary thyroid cancer cells

Thyroid Research ◽

10.1186/s13044-018-0057-6 ◽

2018 ◽

Vol 11 (1) ◽

Cited By ~ 6

Author(s):

Honglai Zhang ◽

Dong Chen

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Papillary Thyroid Cancer ◽

Sodium Iodide ◽

Braf V600e ◽

Papillary Thyroid ◽

Sodium Iodide Symporter ◽

Radioiodine Uptake ◽

Synergistic Inhibition ◽

Thyroid Cancer Cells

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Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs

International Journal of Molecular Sciences ◽

10.3390/ijms19072077 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2077 ◽

Cited By ~ 7

Author(s):

Sabine Wächter ◽

Annette Wunderlich ◽

Brandon Greene ◽

Silvia Roth ◽

Moritz Elxnat ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Sodium Iodide ◽

Thyroid Cancer Cell ◽

Sodium Iodide Symporter ◽

Radioiodine Uptake ◽

Thyroid Cancer Cell Lines ◽

Thyroid Cancer Cells

Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. Methods: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. Results: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. Conclusions: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC.

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Expression of the sodium iodide symporter in differentiated thyroid cancer

Nuklearmedizin ◽

10.1055/s-0038-1625711 ◽

2005 ◽

Vol 44 (03) ◽

pp. 86-96 ◽

Cited By ~ 5

Author(s):

G. Schmitz ◽

L. Füzesi ◽

J. Struck ◽

U. Siefker ◽

A. Hamann ◽

...

Keyword(s):

Thyroid Cancer ◽

Differentiated Thyroid Cancer ◽

Sodium Iodide ◽

Primary Tumour ◽

Sodium Iodide Symporter ◽

Radioiodine Uptake ◽

Imaging Results ◽

Group 2 ◽

Radionuclide Uptake ◽

Group 1

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.

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