Expression of Sodium-Iodide Symporter Depending on Mutational Status and Lymphocytic Thyroiditis in Papillary Thyroid Carcinoma

BACKGROUND AND OBJECTIVES: Sodium-iodine symporter (NIS) is a marker for the degree of differentiation in thyroid cancer. The genetic factors or microenvironment surrounding tumors can affect transcription of NIS. In this study, we investigated the NIS mRNA expression according to mutational status and coexistent lymphocytic thyroiditis in papillary thyroid cancer (PTC). MATERIALS AND METHODS: The RNA expression levels of NIS in the samples from database of The Caner Genome Atlas (TCGA; n=494) and our institute (n=125) were analyzed. RESULTS: The PTCs with the BRAFV600E mutation and the coexistence of BRAFV600E and TERT promoter mutations showed significantly lower expression of NIS (p < 0.001, respectively), and those with BRAF-like molecular subtype also had reduced expression of NIS (p < 0.001). NIS expression showed a positive correlation with thyroid differentiation score (r=0.593, p < 0.001) and negative correlations with expressions of genes involved in ERK signaling (r=−0.164, p < 0.001) and GLUT-1 gene (r=−0.204, p < 0.001). The PTCs with lymphocytic thyroiditis showed significantly higher NIS expression (p=0.013), regardless of mutational status. CONCLUSION: The NIS expression was reduced by the BRAFV600E mutation and MAPK/ERK pathway activation, but restored by the presence of lymphocytic thyroiditis.

Influencing factors on the function of sodium iodide symporter in differentiated thyroid cancer / 中华核医学与分子影像杂志

The expression and function of NIS are the prerequisites of radioactive iodine ( RAI ) treatment for DTC, which in turn determine the iodine uptake and outcome in DTC patients. Studies for the factors that might influence the function of NIS for the development of redifferentiation therapy should be conducted in conjunction with the individualized course of treatment in DTC patients having poor iodine up?take in their thyroid tumors. This review summarizes the factors that influence the function and expression of NIS in these patients.

Alpha-Lipoic Acid Decreases Iodine Uptake in the Rat Thyroid Cell Line FRTL-5 / 대한갑상선학회지

BACKGROUND AND OBJECTIVES: Alpha-lipoic acid (ALA) is a naturally occurring fatty acid with strong antioxidant properties that exerts protective effects against harmful free radical damage. The aim of the present study was to assess the effect of ALA on iodine uptake and expression of sodium iodine symporter (NIS) using FRTL-5 cells. MATERIALS AND METHODS: Cells were treated with ALA for various time and doses, in the presence or absence of thyrotropin (TSH). Cell viability assay, iodine uptake assay and NIS promoter activity assay were performed. RESULTS: ALA increased NIS promoter activity. It showed an additive effect when concomitantly added with TSH. After 48 hours of incubation with ALA in the presence or absence of TSH, there was no difference in iodine uptake according to doses of ALA. After 72 hours of incubation with ALA and TSH, ALA decreased iodine uptake in dose-dependent way. CONCLUSION: ALA induced NIS gene transcription of FRTL-5, but suppressed iodine uptake in the presence of TSH. ALA may suppress iodine uptake through effect for post-translation stage of NIS protein.

Antiproliferation and Redifferentiation in Thyroid Cancer Cell Lines by Polyphenol Phytochemicals

Thyroid carcinogenesis is accompanied by loss of thyroid-specific functions and refractory to radioiodine and thyroid stimulating hormone (TSH) suppression therapy. Redifferentiating agents have been shown to inhibit tumor growth and improve the response to conventional therapy. Polyphenol phytochemicals (PPs) in fruits and vegetables have been reported to inhibit cancer initiation, promotion, progression and induce redifferentiation in selected types. In this study we examined PPs induce redifferentiation in thyroid cancer cell lines. We investigated the effects of genistein, resveratrol, quercetin, kaempferol, and resorcinol on the F9 embryonal carcinoma cell differentiation model. The thyroid cancer cell lines, TPC-1, FTC-133, NPA, FRO, and ARO, displayed growth inhibition in response to genistein, resveratrol, quercetin. We further demonstrated that genistein decreased the dedifferention marker CD97 in NPA cells and resveratrol decreased CD97 in FTC-133, NPA, FRO cells and quercetin decreased CD97 in all cell lines. We observed increased expression of differentiation marker NIS in FTC-133 cells in response to genistein, and resveratrol but no change in NPA, FRO, ARO cells. Quercetin increased or induced NIS in FTC-133, NPA, FRO cells. These findings suggest that PPs may provide a useful therapeutic intervention in thyroid cancer redifferentiation therapy.

Regulation of Sodium-iodine Symporter Expression by Retinoic Acid in Thyroid Cancer Cell Lines / 대한내분비외과학회지

PURPOSE: Response to radioiodine therapy for thyroid cancer is related to the loss of sodium-iodine symporter protein caused by dedifferentiation of thyroid cancer cells. So we aimed to study mRNA expression of CD97, dedifferentiation marker, and sodium-iodine symporter after retinoic acid treatment according to retinoids receptor status. METHODS: Thyroid cancer cell lines; ARO, FRO, NPA, TPO, and FTC133 were prepared. 5µM of all trans retinoic acid were administered to each cell lines and then expression of m RNA for retinoids receptors (RARα, RARβ, RARγ, RXRα, RXRβ, RXRγ), CD97, and Sodium-Iodine symporter by RT-PCR. RESULTS: RARs and RXRs were differently expressed in each cell line. After retinoic acid treatment, relative density of retinoic acid receptor mRNA were increased by time dependently in each cell line except TPO cell line. Expression of CD97 also was decreased in every cell lines (P<0.001). Retinoic acid increased expression of sodium-iodine symporter only in FTC133 cell line (P<0.001), and TSH or forskolin did not enhance NIS expression by retinoic acid. RARβ and RXRγ were expressed only in FTC 133cell line before treatment. Induction of sodium-iodine symporter by retinoids disappeared after RARβ specific antagonist LE135 or pan RXR antagonist PA452 administration. CONCLUSION: Retinoic acid reduced expression of CD97 in five thyroid cancer cell lines. However, retinoic acid could restore sodium-iodine symporter expression in only FTC 133 cell line specifically containing RARβ and RXRγ. Restoration of sodium-iodine symporter expression by retinoic acid is related to RARβ and RXRγ expression.