Zaballos Miguel A, Santisteban Pilar
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Mol Endocrinol. 2013 Jan;27(1):50-62. doi: 10.1210/me.2012-1032. Epub 2012 Nov 16.
TSH and insulin/IGF-I synergistically induce the proliferation of thyroid cells mainly through the cAMP and phosphatidylinositol 3-kinase (PI3K) pathways. However, the events involved in this cooperative induction remain unknown, and molecules that are potentially controlled by both TSH and IGF-I are interesting candidates as integrators of both stimuli. The finding that the PI3K pathway is frequently activated in thyroid malignancies has attracted attention to this pathway in the thyroid field. One of the targets of PI3K is Forkhead box O (FoxO)-1, a widely expressed transcription factor involved in a variety of cellular processes such as differentiation, proliferation, and apoptosis. Here we show that FoxO1 is highly expressed in differentiated rat thyroid cells and human thyroid tissue compared with human thyroid tumor-derived cells and surgically removed thyroid tumors, in which its expression is reduced. In differentiated cells, TSH/cAMP treatment decreases FoxO1 mRNA and protein levels through proteasome activation, whereas both TSH and IGF-I control FoxO1 localization by promoting a rapid exclusion from the nucleus in an Akt-dependent manner. FoxO1 can control p27(KIP1) expression in differentiated and tumor cells of the thyroid. Furthermore, FoxO1 reexpression in tumor cells promotes a decrease in their proliferation rate, whereas FoxO1 interference in differentiated cells increases their proliferation. These data point to an important role of FoxO1 in mediating the effects of TSH and IGF-I on thyroid cell proliferation and provide a link between loss of FoxO1 expression and the uncontrolled proliferation of thyroid tumor cells.
促甲状腺激素（TSH）与胰岛素/胰岛素样生长因子-1（IGF-I）主要通过环磷酸腺苷（cAMP）和磷脂酰肌醇3-激酶（PI3K）途径协同诱导甲状腺细胞增殖。然而，这种协同诱导所涉及的具体事件仍不清楚，而可能受TSH和IGF-I共同调控的分子作为这两种刺激的整合因子是有趣的候选对象。PI3K途径在甲状腺恶性肿瘤中频繁激活这一发现，已引起甲状腺领域对该途径的关注。PI3K的靶点之一是叉头框O（FoxO）-1，它是一种广泛表达的转录因子，参与多种细胞过程，如分化、增殖和凋亡。在此我们表明，与人类甲状腺肿瘤来源的细胞及手术切除的甲状腺肿瘤相比，FoxO1在分化的大鼠甲状腺细胞和人类甲状腺组织中高表达，而在这些肿瘤中其表达降低。在分化细胞中，TSH/cAMP处理通过激活蛋白酶体降低FoxO1的mRNA和蛋白水平，而TSH和IGF-I均通过以Akt依赖的方式促进其快速从细胞核中排出，从而控制FoxO1的定位。FoxO1可调控甲状腺分化细胞和肿瘤细胞中p27（KIP1）的表达。此外，肿瘤细胞中FoxO1的重新表达促进其增殖速率降低，而分化细胞中FoxO1的干扰则增加其增殖。这些数据表明FoxO1在介导TSH和IGF-I对甲状腺细胞增殖的作用中起重要作用，并为FoxO1表达缺失与甲状腺肿瘤细胞不受控制的增殖之间提供了联系。
