Endocrine Abstracts

Objectives: The sodium/iodide symporter (NIS) is a glycoprotein with unique ability of transporting iodine into the thyroid follicle. Apart from the importance in thyroid hormone synthesis, this function of NIS allows the use of radioactive iodine to target residual and metastatic thyroid cancer after thyroidectomy. However, 20–30% of thyroid tumors exhibit lowered expression of NIS, resulting in decreased uptake of radioiodine and inefficient post-surgical therapy. Mechanisms leading to downregulation of NIS are unknown. We hypothesize that this phenomenon results from upregulation of microRNAs, non-coding regulators of gene expression.

Aim: The aim of this study was to identify microRNAs that regulate the expression of NIS and contribute to its deregulation in papillary thyroid carcinoma (PTC).

Methods and results: In silico analysis identified microRNAs putatively binding and regulating NIS. Direct interaction between identified microRNAs and NIS was determined in luciferase assay, in cell lines transfected with synthetic microRNAs and a reporter plasmid with 3′UTR of NIS cloned downstream of luciferase. Significant reduction of luciferase activity was demonstrated for miR-146b-3p (34%, P=0.028), miR-146b-5p (25%, P=0.006), miR-339-5p (21%, P=0.006) and miR-129-2-3p (29%, P=0.004). Real-time PCR performed in 48 pairs of PTC and control, non-cancerous tissue showed a 20-fold decrease of NIS in cancer (P=8×10⁻⁷) together with a 80-fold increase of miR-146b-3p (P=3.3×10⁻⁸) and 140-fold increase of miR-146b-5p (P=2.1×10⁻⁸). Furthermore, NIS levels were negatively correlated with levels of miR-146b-3p (r=−0,40,P=0.01) and miR-146-5p (r=−0.47, P=0.002). Further clinicopathological analysis revealed negative correlation between NIS expression and tumor size (r=−0.32, P=0.026).

Conclusions: This is the first study showing the role of microRNAs in regulation of NIS expression. We propose that downregulation of NIS in PTC results from elevated levels of microRNAs. Since overexpression of miRs is reversal, inhibition of identified microRNAs may result in restoration of NIS expression and reestablishment of radioiodine uptake by thyroid cells.