The Transcriptional Regulation of FOXO Genes in Thyrocytes
The Transcriptional Regulation of FOXO Genes in Thyrocytes
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DOI：
10.1055/s-0042-105153
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发表时间：
2016-09-01
影响因子：
2.2
通讯作者：
Fuehrer, D.
中科院分区：
文献类型：
--
作者：
Franz, F.;Weidinger, C.;Fuehrer, D.
FOXO 转录因子是甲状腺细胞 DNA 损伤修复、增殖和凋亡的关键调节因子。甲状腺恶性肿瘤显示 FOXO 功能受损。在这项研究中，我们研究了甲状腺上皮细胞中 FOXO 亚型的转录调控。在用不同生长因子和 H2O2 刺激的 FRTL-5 细胞中测定 FOXO 亚型（FOXO1、3 和 4）的 mRNA 表达。此外，在 PI3K p110 突变体 FRTL-5 细胞中研究了 PI3K/AKT 信号传导对 FOXO 转录的影响，并在 hFOXO3 过表达的 FRTL-5 细胞中研究了 FOXO 转录对 FOXO 的调节依赖性。最后，在人上皮甲状腺肿瘤中测定了 FOXO 亚型的 mRNA 表达水平。生长因子剥夺诱导了 FRTL-5 细胞中 FOXO1、3 和 4 的转录，而胰岛素刺激则减少了 FOXO1 和 FOXO4 的转录。 PI3K/AKT 级联的抑制会放大 FOXO1 和 FOXO4 的表达。相反，H2O2 和 TSH 不影响甲状腺细胞中的 FOXO 转录。 PI3K p110 的过表达抑制 FOXO3 并诱导 FOXO4 转录。在人类甲状腺肿瘤中，与正常组织相比，甲状腺乳头状癌中的 FOXO1 和 FOXO3 mRNA 水平显着下调。相反，滤泡性甲状腺癌显示 FOXO4 mRNA 显着上调。在本文中，我们证明了 PI3K 信号传导对甲状腺细胞中 FOXO 转录的影响。此外，我们发现，除了之前报道的翻译后 FOXO3 调控的改变之外，甲状腺癌还表现出 FOXO 转录的改变。这些发现可能会增加针对晚期甲状腺癌靶向 PI3K 通路的概念。
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 p110 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 p110 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.