Thyroid cancer remains the most common endocrine malignancy worldwide and its incidence and mortality has increased steadily over the last four decades. In general terms it has a good outcome, however, some patients develop aggressive forms of thyroid cancer that are untreatable and the molecular bases are poorly understood. These aggressive forms have lost NIS (Na/I Symporter) function, one of the most important hallmarks during thyroid cancer progression as it leads to radioiodine-resistant metastastic disease. Our work has contributed to understand the mechanisms involved in iodide uptake repression and tumor progression. We have found that BRAF decreases NIS expression and impairs NIS trafficking to the membrane of follicular thyroid cells, and accordingly causes (RAI)-refractory metastatic disease in patients with papillary thyroid cancer. We demonstrated that the mechanism by which BRAF impairs NIS function is mediated by a TGFβ autocrine loop. Furthermore by next-generation sequencing and gene expression analysis we have identified a master miRNA (miR) regulatory network involved in essential biological process such as thyroid differentiation. Among those miRs, the most abundantly expressed in thyroid tumors is the miR-146b and we found that it binds to the 3-UTR region of both PAX8 and NIS, leading to impaired protein translation and subsequently a reduction of iodide uptake. Besides, we show that miR-146b and PAX8 regulate each other sharing common target genes, thus highlighting a novel regulatory circuit that govern differentiated phenotype in thyroid tumors. In conclusion our work has demonstrated novel mechanisms involved in NIS repression that could be exploited therapeutically for improved treatment of advanced thyroid cancer.