Endocrine Abstracts

Objectives: Apical iodide transporter (AIT) is essential for thyroid homeostasis, functioning both as iodide transporter and a potent tumor suppressor. Its decreased levels observed in thyroid cancer underlie its progression and inefficiency of radioactive iodine treatment, used for ablation of post-operative and metastatic thyroid cancer cells. Mechanisms of AIT downregulation in cancer are largely unknown, but recent data on overexpression of microRNAs in thyroid cancer suggested their possible role in deregulation of AIT.

Aim of the study: The aim of this study was to establish the impact of microRNAs on regulation of AIT expression and to assess the role of deregulation of this process in thyroid carcinogenesis.

Methods and results: MicroRNAs targeting AIT were identified in silico and their interaction with AIT was confirmed in luciferase assay. Significant reduction of luciferase activity was obtained for miR-181a-5p (down 20%, P=0.02), miR-182-5p (18%, P=0.05), and miR-494-3p (15%, P=0.01), indicating binding of these microRNAs to 3′UTR of AIT. Q17-PCR analysis in 48 PTC and non-tumorous paired tissue samples revealed a 67-fold decrease of AIT (P=2×10⁻⁷) in PTC and a concomitant upregulation of miR-181a-5p (1.67-fold, P=0.001) and miR-182-5p (2.03-fold, P=0.002). AIT expression was additionally 4.79-fold lowered (P=0.001) in presence of BRAFV600F mutation. AIT levels negatively correlated with tumor size (r=−0.29, P=0.03, n=54). Q17-PCR analysis of 19 thyroid adenomas showed a 2.24-fold decrease of AIT, accompanied by upregulation of miR-181a-5p (1.8-fold, P=0.02), miR-182-5p (5.4-fold, P=0.05), and miR-494-3p (6.1-fold, P=0.01). Downregulation of AIT was correlated with upregulation of its downstream effector, antiapoptotic survivin (r=−0.45, P=0.055).

Conclusions: This is the first study showing microRNA-dependent regulation of AIT expression and its aberrances in thyroid malignancies. Modulating the levels of miR-181a-5p, miR-182-5p, and miR-494-3p could be used for restoration of AIT and reversal of carcinogenic process, as well as to reestablishment of radioiodine uptake by thyroid cells.