Abstract
NIS is a potent iodide transporter encoded by the SLC5A5 gene. Its expression is reduced in papillary thyroid carcinoma (PTC). In this study we analyzed the impact of miR-181a-5p on NIS expression in the context of PTC. We used real-time PCR to analyze the expression of SLC5A5 and miR-181a-5p in 49 PTC/normal tissue pairs. Luciferase assays and mutagenesis were performed to confirm direct binding of miR-181a-5p to the 3′UTR of SLC5A5 and identify the binding site. The impact of modulation of miR-181a-5p using appropriate plasmids on endogenous NIS and radioactive iodine accumulation was verified. We confirmed downregulation of SLC5A5 and concomitant upregulation of miR-181a-5p in PTC. Broadly used algorithms did not predict the binding site of miR-181a-5p in 3′UTR of SLC5A5, but we identified and confirmed the binding site through mutagenesis using luciferase assays. In MCF7 and HEK293-flhNIS cell lines, transfection with mir-181a-expressing plasmid decreased endogenous SLC5A5, whereas silencing of miR-181a-5p increased it. We observed similar tendencies in protein expression and radioactive iodine accumulation. This study shows for the first time that miR-181a-5p directly regulates SLC5A5 expression in the context of PTC and may decrease efficacy of radioiodine treatment. Accordingly, miR-181a-5p may serve as an emerging target to enhance the efficacy of radioactive iodine therapy.
Highlights
The ability of the thyroid gland to accumulate iodide has been known since the end of the 19th century [1]
The Expression of SLC5A5 Is Lowered in papillary thyroid carcinoma (PTC)
The patients represented all stages of the disease excluding IVB; 44 (90%) tumors represented the classic variant of PTC (PTCcv) and 5 (10%) were the follicular variant of PTC (PTCfv)
Summary
The ability of the thyroid gland to accumulate iodide has been known since the end of the 19th century [1]. Diagnostic use of radioiodine dates back to the 1930s [2], and since the 1940s radioiodine has been used for the treatment of thyroid carcinoma [3]. The capability of thyroid to collect iodide, necessary for fulfilling its physiological function, which is synthesis of iodine-containing thyroxin and triiodothyronine [4], results from the activity of mainly one protein—sodium/iodide symporter (NIS). NIS is a multi-pass membrane glycoprotein located on the basolateral membrane of thyroid follicular epithelial cells, which is able to concentrate iodine, creating an up to 40-fold gradient [5]. It consists of 643 amino acids and is encoded by the SLC5A5 gene [6]. Soon after its molecular characterization, it was found that expression of NIS is reduced in thyroid tumors compared to normal thyroid tissue [7]
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