In principle, undifferentiated thyroid cancers as well as nonthyroid cancers can concentrate and, thus, be treated with radioiodine after transfection with the human sodium iodide symporter (hNIS) gene.
Apart from these therapeutic and diagnostic perspectives the availability of the NIS gene will also open new opportunities to develop sensitive and homologous diagnostic test systems to identify factors involved in autoimmune thyroid disease, evolution of goitre, adenoma and thyroid cancer as well as NIS-directed new drugs.
Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.
These targets include the proto-oncogenes BRAF and RET, known to be common mutations in thyroid cancer; vascular endothelial growth factor receptor and platelet-derived growth factor receptor, associated with angiogenesis; and the sodium-iodide symporter, with the aim of restoring its expression and hence radioactive iodine uptake.
The transcriptional regulation of the human sodium/iodide symporter (NIS) gene in normal and transformed thyroid cells is a crucial issue in attempting to restore iodide uptake and use radioiodine as a therapeutic treatment of thyroid cancer.
Radioiodine whole body scan (WBS), related to sodium iodide symporter (NIS) function, is widely used to detect recurrence/metastasis in postoperative patients with thyroid cancer.
NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane.
In conclusion, our study has uncovered the existence of a miR-146b-3p/PAX8/NIS regulatory circuit that may be exploited therapeutically to modulate thyroid cell differentiation and iodide uptake for improved treatment of advanced thyroid cancer.
Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFbeta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression.
These data support further translational studies with <sup>18</sup>F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.
In summary, our results elucidate a pump-independent, protumorigenic role for NIS in thyroid cancer via its cross-talk with PTEN signaling.<b>Significance:</b> A novel pump-independent protumorigenic role of nonmembranous NIS challenges the presumption that radioiodine treatment of thyroid cancer is ineffective when transmembrane NIS is not expressed.<i></i>.
The sodium-iodide symporter (NIS), which mediates iodide uptake into thyroid cells, and is the molecular basis of radioiodine imaging and therapy in thyroid cancer, is also expressed in a large portion of breast tumors.
Radioactive iodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by the sodium iodide symporter (NIS), is the first rate-limiting step in iodide accumulation which provides a mechanism for effective radioiodide treatment for patients with thyroid cancer.
Several investigators have shown that gene transfer of NIS into a variety of cell types confers increased radioiodine uptake by up to several hundredfold that of controls in nonthyroid cancers as well as in thyroid cancer.
These studies evaluating the etiological roles of these factors in linking breast and thyroid cancer might also improve our understanding and identify new therapeutic approaches, such as sodium/iodide symporter-mediated radioiodine therapy and thyroid-stimulating hormone receptor antagonists, for breast cancer.
Radioiodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by a plasma membrane transporter, sodium iodide symporter (NIS), provides a first step mechanism for thyroid cancer detection by radioiodide injection and effective radioiodide treatment for patients with invasive, recurrent, and/or metastatic thyroid cancers after total thyroidectomy.
Noninvasive imaging of iodide uptake via the sodium/iodide symporter (NIS) has received great interest for evaluation of thyroid cancer and reporter imaging of NIS-expressing viral therapies.
Cloning of the NIS gene and the development of specific NIS antibodies have allowed the characterization of the pathogenic role of NIS in thyroid cancer, thyroid autoimmune diseases, congenital hypothyroidism and other, non-thyroidal human diseases.