Abstract
Iodide (I-) is an essential constituent of the thyroid hormones triiodothyronine (T3) and thyroxine (T4), and the iodide concentrating mechanism of the thyroid gland is essential for the synthesis of these hormones. In addition, differential uptake of iodine isotopes (radioiodine) is a key modality for the diagnosis and therapy of thyroid cancer. The sodium dependent iodide transport activity of the thyroid gland is mainly attributed to the functional expression of the Na+/I- Symporter (NIS) localized at the basolateral membrane of thyrocytes. In this paper, we review and summarize current data on molecular characterization, on structure and function of NIS protein, as well as on the transcriptional regulation of NIS encoding gene in the thyroid gland. We also propose that a better and more precise understanding of NIS gene regulation at the molecular level in both healthy and malignant thyroid cells may lead to the identification of small molecule candidates. These could then be translated into clinical practice for better induction and more effective modulation of radioiodine uptake in dedifferentiated thyroid cancer cells and in their distant metastatic lesions.
Highlights
Biological Significance of Iodide TransportIodine (127I) is the heaviest element metabolized in biological material
Thyroid diseases characterized by excess or deficient production of thyroid hormones, enlargement of the gland, presence of aberrant nodules, neoplastic proliferation, and auto-immune syndromes are frequently encountered in endocrinological practice, and thyroid ailments in endocrinology clinics are surpassed in numbers only by diabetes
Since the mid 1940’s, differential expression of thyroid Na+/I- Symporter (NIS) in different pathological conditions leading to a differential biodistribution of iodide isotopes in tissues with different histological and pathological characteristics have made the radioiodide transport system, NIS, a crucial factor for the diagnosis, treatment, or evaluation of pathological thyroid conditions
Summary
Iodine (127I) is the heaviest element metabolized in biological material. It is a limiting element for the synthesis of covalently bound iodine-containing thyroid hormones, which are essential for proper growth and development of many organs in vertebrates [1,2]. Concerning possibilities of a direct action via ERα, the authors detected a novel ERE sequence conserved in human, rat and mouse genomes in proximity (9 base pairs) of NIS TATA element, with the capacity to activate gene expression in luciferase reporter assays in analyzed ER-positive mammary cell line models [69] Such a close localization of TATA and ERE elements in NIS promoter is very unusual considering that all previously characterized ERE elements were shown to be localized at relatively distant positions to transcription start sites in corresponding genes [ varying remarkably between +23,088 and -2687 [70]]. The up-regulatory effect of tRA on thyroid NIS expression was established at the molecular level with several clinical trials successfully demonstrating RA redifferentiation effects in previously dedifferentiated thyroid tumors and their metastases [87,88,89]
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