The Role of the NIS (SLC5A5) Gene in Papillary Thyroid Cancer: A Systematic Review

Table 1

Comparison of different studies of the role of NIS in papillary thyroid cancer.

Author	Title	Objective	Year	Country	Sample	Laboratorial test	Results	value
Riesco-Eizaguirre et al. [17]	The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na^+/I^− targeting to the membrane	To investigate the role of BRAFV600E and MEK-ERK in the dedifferentiation of the thyroid	2006	Spain		Immunohistochemistry	The NIS staining was either negative or weakly positive and not localized to the membrane.
Lee et al. [18]	Relationship of sodium/iodide symporter expression with I131 whole body scan uptake between primary and metastatic lymph node papillary thyroid carcinomas	To evaluate the total and membranous NIS expression in the PTC papillary tissue, to associate it with the NIS expression between the PTC tissues of the primary and metastatic lymph node (LN), and to relate the NIS expression to the full-scan iodine-131 uptake between the primary tissues and metastatic lesions of the LN PTC	2007	Korea		Immunohistochemistry	In cancer cells, the staining was located in the plasma membrane and cytoplasm.	NA
							In primary PTC, the positivity of NIS expression was higher between healthy cells and cancer cells.
Smith et al. [19]	Methylation status of genes in papillary thyroid carcinoma	To determine the methylation status of the gene promoter regions and to associate with tumor factors or outcome measures among patients with papillary thyroid carcinoma	2007	USA		MSP-PCR	The NIS gene was methylated in the malignant tissue more often than in controls. In all controls, the promoter regions for NIS were not methylated.
							There was no statistical difference in the proportion of nodular metastasis between the methylated and unmethylated NIS samples.
							NIS methylation in tumor cells was not accompanied by methylation in adjacent normal tissue.	NA
Mian et al. [41]	Molecular characteristics in papillary thyroid cancers (PTCs) with no 131I uptake	To characterize at the molecular level a subset of PTC without iodine-131 uptake	2008	Italy		qPCR	NIS gene expression was lower in PTC than in normal tissue.	NA
							Patients with metastases in the neck region without 131I uptake revealed only a slight decrease in NIS transcripts compared to patients with the primary tumor.
Oler and Cerutti [20]	High prevalence of BRAF mutation in a Brazilian cohort of patients with sporadic papillary thyroid carcinomas	To investigate the mutation status of BRAF and to correlate it with clinicopathological characteristics and expression of NIS and TSH-R	2009	Brazil		qPCR	The expression of NIS was lower in the BRAFV600E group compared to the BRAFwt group in patients with classic PTC.
							The same also happened in the follicular variant.
Morari et al. [21]	Use of sodium iodide symporter expression in differentiated thyroid carcinomas	To investigate the use of NIS mRNA and protein expression as a diagnostic and/or prognosis marker in patients with differentiated thyroid cancer (TCD)	2011	Brazil		Immunohistochemistry/qPCR	All 13 patients with DTC who died were NIS negative and had low mRNA expression.	NA
							The NIS expression was lower in PTC BRAFV600E.
							The data analyzed did not identify individuals with worse prognosis.
Qin et al. [22]	Correlation of clinicopathological features and expression of molecular markers With prognosis after 131I treatment of differentiated thyroid carcinoma	To identify molecular markers associated with patients with differentiated thyroid carcinoma (DTC) and to determine the existence of a correlation between clinicopathological characteristics or molecular markers with the result of iodine therapy	2012	China		Immunohistochemistry	Positive NIS expression was different in patients with DTC.
Moon et al. [23]	Comparison of 18F-fluorodeoxyglucose uptake with the expressions of glucose transporter type 1 and Na^+/I^− symporter in patients with untreated papillary thyroid carcinoma	To compare the uptake of FDG-F18 with the expression of GLUT1 and NIS in tumors of patients diagnosed with PTC undergoing curative surgery	2013	Korea		PET/CT	The SUV in lesions with NIS-negative expressions was higher than that in the lesions with positive expression of NIS.
Kleiman et al. [24]	Thyroid-stimulating hormone increases iodine uptake by thyroid cancer cells during BRAF silencing	To evaluate the combined effect of BRAF inhibition and TSH supplementation on iodine-131 uptake in thyroid cancer cells with BRAFV600E	2013	USA		qPCR	The expression of NIS in the group of patients with thyroid cancer (of which 86.5% were PTC) with mutation was lower.
Wang et al. [25]	Differential expression of the Na+/I-symporter protein in thyroid cancer and adjacent normal and nodular goiter tissues	To determine whether the NIS protein was differentially expressed in papillary thyroid cancer and several surrounding tissues	2013	China		Immunohistochemistry	NIS protein was expressed especially in the cytoplasm.
Wei et al. [26]	Low expression of sodium iodide symporter expression in aggressive variants of papillary thyroid carcinoma	To investigate the difference of NIS expression in aggressive variants, including high cell variant (TCV), diffuse sclerosing variant (DSPTC), and conventional PTC	2014	China		Immunohistochemistry	In all conventional NIS-positive PTCs, they showed strong staining for tissue identification. NIS expression was identified mainly in the membrane and in the nucleus and was also observed in the cytoplasm in some cases of PTC.
Kim et al. [27]	Expression patterns of glucose transporter-1 gene and thyroid specific genes in human papillary thyroid carcinoma	To compare the differentiation of PTC with the expression of the glucose-1 transporter gene (Glut-1), in addition to other thyroid specifics	2014	Korea		RT-PCR	The NIS expression in patients with well-differentiated cancer was higher compared to that in patients with less-differentiated cancer.
							Negative correlation between NIS gene expression and Glut-1 in PTC patients (r = 0.60)
							Nevertheless, in these patients, there was a positive correlation between NIS and TG expression (r = 0.52); NIS and pendrin (r = 0.77)
Choi et al. [28]	B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1	To analyze whether NIS expression was correlated with the expression of BRAFV600E as well as the existence of the methylation of the CpG island	2014	Korea		Immunohistochemistry/qPCR	NIS staining in the plasma membrane region of the normal thyroid follicle and was reduced in PTC BRAFV600E. 37% of PTC tissues presented diffuse cytoplasmic staining.	NA
							NIS expression is downregulated.	NA
							NIS expression was reduced when BRAFV600E was expressed in normal primary thyrocytes isolated from tissues via lentivirus transduction.	NA
							Thyrocytes expressing BRAFV600E do not efficiently absorb the iodide.
							Inhibition of NIS expression by inducing methylation of the CpG island in the NIS promoter region. The expressions DNMT1 and NIS were inversely correlated.
Sponziello et al. [29]	PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells	To analyze the expression of PDE5 in a series of PTC carcinomas with or without BRAFV600E mutation, classified according to the ATA risk criteria	2015	Italy		qPCR and MTT viability test	Higher levels of PDE5A expression in PTC patients compared with controls. NIS mRNA expression levels were decreased in patients with PTC.
Rosignolo et al. [30]	Reduced expression of THRβ in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression	To analyze the expression of THRβ, NIS, TPO, Tg, and TSH-R mRNA in PTC surgical samples	2015	Italy		qPCR	Positive correlation was detected with THRβ levels and NIS mRNA levels (ra = 0.3771).
							The levels of NIS expression in tumor tissues are lower than the corresponding normal.
							Mutation in the BRAFV600E gene is associated with decreased NIS expression.
Ma et al. [31]	FoxP3 in papillary thyroid carcinoma induces NIS repression through activation of the TGF-β1/Smad signaling pathway	Hypothesize that FoxP3 can inhibit NIS membrane expression and cleavage by inducing TGF-β1 secretion and subsequent activation of the Smad signaling pathway	2016	China		Immunohistochemistry	NIS staining was located almost exclusively on the plasma membrane in normal thyroid tissues; however, the staining was less intense in tumor tissues.	NA
							The FoxP3-positive group had a lower rate of NIS staining.
						qPCR	NIS transcript levels were significantly reduced in the tumor sample.
							NIS transcript levels decreased and reached the minimum concentration in 10 ng/mL TGF-beta1.
							NIS protein levels were also strongly suppressed by TGF-β1, and there was decrease in relation to the control group.
Dong et al. [32]	Effects of BRAF^V600E mutation on Na^+/I^- symporter expression in papillary thyroid carcinoma	To discuss the association of BRAFV600E mutation and NIS expression in PTC tissue and the possible implications on iodine therapy	2016	China		qPCR	The BRAFV600E mutation did not show inhibitory effect on NIS expression.
						Immunohistochemistry	After adjusting for confounding factors, the mutated PTC BRAFV600E showed lower NIS expression than the wild type in the cases without Hashimoto thyroiditis.
Yazgan et al. [33]	The correlation of sodium iodide symporter and BRAFV600E mutation in classical variant papillary thyroid	To correlate the BRAFV600E mutation and the expression of NIS in PTC classical variant patients	2016	Turkey		qPCR	Functional expression of NIS was greater.
							Nonfunctional expression of NIS was lower.
Stasiołek et al. [34]	The molecular effect of diagnostic absorbed doses from 131I on papillary thyroid cancer cells in vitro	Obtain information on possible cellular and molecular mechanisms underlying the stunning phenomenon	2017	Poland	—	qPCR/K1 cell culture	Expression of the NIS protein in the K1 cells analyzed after 24 h incubation with iodine-131 showed a positive regulation in groups of the lower (5 Gy) and higher (20 Gy) doses of radioactive iodine.
							Statistically significant changes in the 8-oxo-dG level were observed in K1 cells treated with the lowest 131I (5 Gy) dose compared to the control, even 96 h after treatment, indicating a prolonged accumulation of DNA damage even after the end of irradiation with iodine-131.