FOXO
transcription factors are key regulators of DNA damage repair, proliferation and apoptosis in thyrocytes. Thyroid
malignancies show impaired FOXO function. In this study, we investigated the transcriptional regulation of FOXO
isoforms in thyroid epithelial cells.
mRNA expression of FOXO
isoforms (FOXO1, 3 and 4) was determined in FRTL-5 cells stimulated with different
growth factors and H2O2. Furthermore, the impact of PI3K/AKT signalling on FOXO transcription was investigated in PI3K p110α mutant FRTL-5 cells and regulatory dependence of FOXO transcription on FOXO was studied in FRTL-5 cells with hFOXO3 overexpression. Finally,
mRNA expression levels of FOXO
isoforms were determined in human epithelial thyroid tumours.
Growth factor deprivation induced transcription of FOXO1, 3 and 4, whereas
insulin stimulation decreased FOXO1 and FOXO4 transcription in FRTL-5 cells. Inhibition of the PI3K/AKT cascade amplified FOXO1 and FOXO4 expression. In contrast, H2O2 and TSH did not influence FOXO transcription in thyrocytes. Overexpression of PI3K p110α inhibited FOXO3 and induced FOXO4 transcription. In human thyroid tumours, FOXO1 and FOXO3
mRNA levels were significantly downregulated in
papillary thyroid carcinoma when compared to normal tissues. In contrast,
follicular thyroid carcinomas showed significant upregulation of FOXO4
mRNA.In this paper, we demonstrate an influence of PI3K signalling on FOXO transcription in thyrocytes. Moreover, we show that
thyroid cancers exhibit alterations in FOXO transcription besides the previously reported alterations in posttranslational FOXO3 regulation. These findings may add to the concept of targeting the PI3K pathway in advanced
thyroid cancers.