Cell differentiation occurs as a result of the concerted activation of multiple signalling pathways in response to environmental stimuli. We have stu died the role elicited by several growth factors and oncogenes in the control of Sodium/Iodide Symporter (NIS) gene expression, a thyroid differentiation marker. Our results have shown that IGF1/PI3K and TGFbeta/Smads inhibit NIS gene transcription induced by TSH/cAMP, a mechanism mediated by the inhibition of Pax8 binding to NIS enhancer. Concerning oncogenes, we have shown that BRAFV600E, the most frequent genetic event in thyroid cancer, sharply impaired both NIS expression and targeting to membrane and, surprisingly, this impairment was not totally dependent on the MEK-ERK pathway. Interestingly, we have show that BRAF-induced NIS repression is dependent on the operation of an autocrine loop involving TGFbeta, whose secretion was induced by BRAFV600E. Subsequently, inhibition of TGFβ-receptor or its kinase activity clearly reinduced NIS functional activity in thyroid cells cancer. We conclude that the crosstalk and cooperation between multiple pathways may have important implications in thyroid differentiation, providing new insights of the mechanisms underlying tumorigenesis.
03 - 07 May 2008
European Society of Endocrinology