The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues

The sodium/iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years, radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression, and the role that miRNAs play in fine-tuning NIS after being transcribed. A review on how hormones, cytokines, and iodide itself regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity.The authors want to thank the support of the following Grants: PID2019-105303RB-I00/AEI/10.13039/501100011033 from MICIN and B2017/BMD3724 Tironet2 from Comunidad de Madrid (to P S); MICIU/FEDER RTI2018-099343-B-100 (to A D l V). The Asociación Española Contra el Cancer (AECC); GCB141423113) jointly awarded to P S and G R-E. PS, G R-E, and A D l V, belong to CIBERONC ISCIII