Endocrine Abstracts

The Sodium Iodide Symporter (NIS) is responsible for active transport of iodide into thyroid cells. Its expression in thyroid tumors allows the use of radioactive iodine (131I) as co-adjuvant therapeutic tool to eliminate remaining tumor cells and metastases after total thyroidectomy. Nevertheless, certain subsets of patients with advanced forms of thyroid cancer lose the ability to respond to radioiodine therapy, which drastically reduces their survival rates. Recent studies have implicated the Rac1/p38 pathway in the stimulation of NIS expression through a mechanism that remains unclear. Additionally, the overexpression of RAC1b, a hyperactive splicing variant of RAC1, was recently shown to be overexpressed in a subset of papillary thyroid carcinomas carrying the activating mutation BRAFV600E and to be associated with unfavorable outcome. BRAFV600E mutation, in turn, has been associated with the downregulation of NIS. Here, we further investigate the role of RAC1/RAC1b on NIS expression levels, and developed new cellular models to functionally assess the impact of these GTPases on NIS-mediated iodide uptake. To evaluate whether RAC1b has a role in NIS expression modulation, we determined NIS transcript levels in a cohort of 64 follicular cell-derived thyroid tumors, comparing tumors presenting RAC1b overexpression (n=32) to those that did not (n=32). RAC1b-overexpressing tumors were defined as those with expression levels above a defined threshold (corresponding to the mean value plus two SDs of RAC1b expression level in a normal thyroid group). RAC1b and NIS expression was assessed by quantitative RT-PCR. We found that samples negative for RAC1b expression presented higher levels of NIS in comparison to RAC1b-overexpressing samples (4.402±1.271 vs 1.916±0.5423, respectively; P=0.0384, two-tailed Student’s t-test). Thus, our results show an inverse correlation between RAC1b and NIS expression levels, suggesting that RAC1b might antagonize RAC1 effectiveness at stimulating NIS expression. To further explore the impact of RAC1/1b signalling on NIS expression regulation, we established a halide-sensitive YFP-based reporter in a normal thyroid cell line system, allowing us to detect differences on iodide influx upon TSH stimulation. Our preliminary results support the relevance of further studying the impact of RAC1/1b on NIS regulation.