Int J Thyroidol.  2018 Nov;11(2):152-159. 10.11106/ijt.2018.11.2.152.

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

• Song YS
• Park YJ

• KMID: 2448986
• DOI: http://doi.org/10.11106/ijt.2018.11.2.152

Abstract

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.

Keyword

Sodium-iodine symporter; BRAF(V600E) mutation; Lymphocytic thyroiditis; Papillary thyroid carcinoma

MeSH Terms

Genome
Ion Transport*
RNA
RNA, Messenger
Thyroid Gland*
Thyroid Neoplasms*
Thyroiditis, Autoimmune*
RNA
RNA, Messenger

Figure

• 

  Fig. 1 NIS mRNA expression according to mutational status. (A–E) The mRNA expression levels of SLC5A5 (NIS) from The Cancer Genome Atlas (TCGA) database. Median expression levels of NIS according to mutational status of BRAFV600E (A; wild-type, n=260; mutant-type, n=234), RAS (B; wild-type, n=442; mutant-type, n=52), TERT promoter (C; wild-type, n=348; mutant-type, n=39), their combination (D; none, n=107; BRAF, n=198; RAS, n=43; TERT, n=5; BRAF+TERT, n=28; RAS+TERT, n=6), and molecular subtype (E; BRAF-like, n=272; RAS-like, n=119). (F–J) The mRNA expression levels of NIS from the Seoul National University Hospital (SNUH) database. Median expression levels of NIS according to mutational status of BRAFV600E (F; wild-type, n=58; mutant-type, n=67), RAS (G; wild-type, n=101; mutant-type, n=24), TERT promoter (H; wild-type, n=84; mutant-type, n=12), their combination (I; none, n=15; BRAF, n=50; RAS, n=19; TERT, n=3; BRAF+TERT, n=7; RAS+TERT, n=2), and molecular subtype (J; BRAF-like, n=81; RAS-like, n=35). SLC5A5: NIS gene, WT: wild-type, MUT: mutant-type, B+T: BRAF+TERT, R+T: RAS+TERT, RPKM: reads per kilobase million, FPKM: fragments per kilobase million

• 

  Fig. 2 Associations of NIS mRNA expression with thyroid differentiation score, ERK signature, and GLUT-1 mRNA expression. (A–C) The correlations between SLC5A5 (NIS) mRNA expression and thyroid differentiation score (TDS) (A), ERK signature (B), SLC2A1 (GLUT-1) mRNA expression (C) from TCGA database. The mRNA expression levels were presented as reads per kilobase million (RPKM). r=the Pearson correlation coefficient. (D) The patterns of NIS expression, TDS, ERK signature, and GLUT-1 expression according to mutational status from TCGA database. SLC5A5: NIS gene, TDS: thyroid differentiation score, SLC2A1: GLUT-1 gene

• 

  Fig. 3 Effects of lymphocytic thyroiditis on NIS mRNA expression. (A–E) The mRNA expression levels of SLC5A5 (NIS) from TCGA database. Median expression levels of NIS according to the status of LT (A; LT(−), n=233; LT(+), n=114), BRAFV600E and LT (B; B(−)LT(−), n=109; B(−)LT(+), n=47; B(+)LT(−), n=124; B(+)LT(+), n=67), RAS and LT (C; R(−)LT(−), n=211; R(−)LT(+), n=113; R(+)LT(−), n=22; R(+)LT(+), n=1), TERT and LT (D; T(−)LT(−), n=157; T(−)LT(+), n=85; T(+)LT(−), n=20; T(+)LT(+), n=6), and molecular subtype and LT (E; BL/LT(−), n=142; BL/LT(+), n=80; RL/LT(−), n=38; RL/LT(+), n=87). (F–J) The mRNA expression levels of NIS from the SNUH database. Median expression levels of NIS according to the status of LT (F; LT(−), n=72; LT(+), n=53), BRAFV600E and LT (G; B(−)LT(−), n=36; B(−)LT(+), n=22; B(+)LT(−), n=36; B(+)LT(+), n=31), RAS and LT (H; R(−)LT(−), n=54; R(−)LT(+), n=47; R(+)LT(−), n=18; R(+)LT(+), n=6), TERT and LT (I; T(−)LT(−), n=51; T(−)LT(+), n=33; T(+)LT(−), n=8; T(+)LT(+), n=4), and molecular subtype and LT (J; BL/LT(−), n=40; BL/LT(+), n=41; RL/LT(−), n=28; RL/LT(+), n=7). SLC5A5: NIS gene, LT: lymphocytic thyroiditis, B: BRAFV600E mutation, R: RAS mutations, T: TERT promoter mutations, BL: BRAF-like, RL: RAS-like, RPKM: reads per kilobase million, FPKM: fragments per kilobase million

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