Phosphorylated IGF-IR (pIGF-IR) receptor expression is lost in most poorly differentiated follicular thyroid cancers (FTC). In contrast, expression of Inhibitors of Differentiation (Id) proteins is highest in malignant thyroid tissue, suggesting that IGF-IR signaling may regulate Id expression in FTC. To test this hypothesis, IGF-IR signaling was up-regulated in a follicular thyroid cancer cell line that had low to undetectable levels of pIGF-IR. Indeed, restoration of wild type IGF-IR (wt-IGF-IR) signaling resulted in transient repression of Id1 and Id2 with a concomitant increase in nuclear pStat3 levels in response to IGF-I treatment. Constitutive activation of the receptor on the other hand resulted in constitutive activation of pStat3, pMAPK and prolonged repression of Id1. Id2 expression, however, was transiently increased in these cells and then steadily declined. Furthermore, when a panel of thyroid carcinoma cell lines was analyzed for pIGF-IR expression and their endogenous Id1 and Id2 levels, cells with highest levels of pIGF-IR had the lowest levels of Id1 and Id2 mRNA. Our results indicate that Id1 expression may be tightly regulated through IGF-IR signaling in differentiated FTC. However, its expression may be up-regulated in poorly differentiated thyroid carcinoma cells when control is lost via loss of IGF-IR signaling or by accumulation of additional mutations that can induce its expression independent of MAPK or PI-3K pathways. Our data provides a possible molecular mechanism to explain the up-regulation of Id1 in poorly differentiated FTC.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA