FOXO3a: a novel player in thyroid carcinogenesis?
FOXO3a: a novel player in thyroid carcinogenesis?
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DOI：
10.1677/erc-07-0283
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发表时间：
2009-03-01
影响因子：
3.9
通讯作者：
Fuhrer, Dagmar
中科院分区：
文献类型：
--
作者：
Karger, Stefan;Weidinger, Carl;Fuhrer, Dagmar
叉头盒转录因子FOXO3a最近被认为是氧化应激诱导细胞周期停滞或凋亡的细胞反应的中心调节因子。本研究的目的是研究FOXO3a在甲状腺中的调节，并确定FOXO3a活性的改变是否发生在甲状腺癌变过程中。在体外，我们证明了FOXO3a的活性受到PI3K/Akt级联的负调控，促进了FOXO3a的磷酸化和胞质积累，靶基因p27kip(CDKN1B)和Bim(BCL2L11)的转录减少，但GADD45A的表达增加。相反，我们发现过氧化氢暴露激活了甲状腺细胞中的FOXO3a，JNK(MAPK8)介导的FOXO3a的核积累和细胞周期抑制基因p27kip和GADD45A的表达增加。在体内，我们观察到FOXO3a在分化型甲状腺癌中显著的胞浆积聚，而在滤泡状腺瘤和正常甲状腺组织中仅有核积聚。此外，这种胞浆中FOXO3a的积聚与甲状腺恶性肿瘤中磷酸化Akt表达的增加有关，并伴随着FOXO靶标p27kip和Bim的表达减少以及GADD45A mRNA在甲状腺癌中的表达增加。我们的数据表明，FOXO3a是甲状腺细胞应激反应的一个新的参与者，调节甲状腺细胞的命运，要么存活，要么经历凋亡。此外，依赖于PI3K的FOXO3a失活可能是甲状腺癌细胞尤其是滤泡性甲状腺癌逃避凋亡的一种新的病理机制。
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 p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H2O2 exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. 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 p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.