Endocrine Abstracts

The presence of differentiated follicular thyroid cells in thyroid cancer is critical for the antitumor response to radioactive iodide treatment, and loss of the differentiated phenotype is a key hallmark of iodide-refractory metastatic disease. Thus, one of the objective of our laboratory is to study the signals and molecular mechanisms involved in thyroid differentiation in cancer. Among genes responsible of thyroid differentiated phenotype are the transcription factor PAX8 and its target gene SLC5A5, also named as NIS (Na/I Symporter), which function is to uptake iodide. It is well accepted that the RET-RAS-BRAF-ERK signaling pathway leads to thyroid cellular transformation being the BRAF mutation the most frequent genetic event that confers aggressive biological behavior to papillary thyroid cancer (PTC). We have shown that BRAF impairs NIS function by a mechanism involving the TGFβ/Smad signaling and accordingly causes radioiodide-resistant metastasis. In addition TGFβ has a strong cooperative effect with ERK signal in BRAF-induced epithelial mesenchymal transition (EMT), migration, and invasion. We have generated an orthotopic mouse model of thyroid cancer to study primary tumor formation and its metastases and how the inhibition of the TGFbeta pathway could abolish metastases and recover Iodide uptake.

By Next Generation Sequencing we have identified the miRNome and characterized the miRNAs (miRs) regulatory network of normal thyroid and PTC samples unveiling that the most abundant deregulated miRs in PTC regulates genes essential for thyroid differentiation. Among these miRs are the mature products of miR-146b (miR-146b-5p and -3p) that targets genes involved in iodide metabolism such as PAX, NIS and IYD (DEHAL1), the iodotyrosine deiodinase that controls the recycling of iodide for thyroid hormone synthesis. In addition, miR-146b-5p targets DIO2, the iodothyronine deiodinase that converts T4 into T3. We have performed functional studies found that miR-146b-3p binds to the 3′UTR of PAX8 and NIS leading to impaired protein translation and a subsequent reduction in iodide uptake. Interestingly miR-146b and PAX8 regulate each other and share common target genes, thus highlighting a novel regulatory circuit that governs the differentiated phenotype of PTC.

In summary, all these data describe molecular determinants that may be exploited therapeutically to modulate thyroid cell differentiation and iodide uptake for improved treatment of advanced thyroid cancer.