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S Karger, Department of Internal Medicine, University of Leipzig, Leipzig, 04103, Germany
C Weidinger, Department of Internal Medicine, University of Leipzig, Leipzig, Germany
K Krause, Department of Internal Medicine, University of Leipzig, Leipzig, Germany
S Sheu, Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany
T Aigner, Institute of Pathology, University of Leipzig, Leipzig, Germany
O Gimm, Department of Surgery, University of Halle-Wittenberg, Halle, Germany
K Schmid, Essen, Germany
H Dralle, Halle, Germany
D Fuehrer, Department of Internal Medicine, University of Leipzig, Leipzig, Germany

Correspondence: Stefan Karger, Email: stefan.karger{at}medizin.uni-leipzig.de

Abstract

The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip1 and Bim but increased expression of Gadd45. In contrast, we show that H2O2 exposure activates FOXO3a in thyrocytes with JNK mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip1 and Gadd45. In vivo we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers, versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip1 and Bim and an increase in Gadd45 mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the fate of the thyrocyte either to survive or to undergo apoptosis. Furthermore, the PI3-kinase dependent FOXO3a inactivation might be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.