Targeted Foxe1 Overexpression in Mouse Thyroid Causes the Development of Multinodular Goiter But Does Not Promote Carcinogenesis
Targeted Foxe1 Overexpression in Mouse Thyroid Causes the Development of Multinodular Goiter But Does Not Promote Carcinogenesis
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DOI：
10.1210/en.2015-2066
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发表时间：
2016-05-01
期刊：
影响因子：
4.8
通讯作者：
Mitsutake, Norisato
中科院分区：
文献类型：
--
作者：
Nikitski, Alyaksandr;Saenko, Vladimir;Mitsutake, Norisato
最近的全基因组关联研究发现，叉头盒E1基因(FOXE1)基因座上的几个单核苷酸多态与甲状腺癌的风险密切相关。此外，我们最近的工作表明FOXE1在乳头状甲状腺癌中过表达。为了评估Foxe1在甲状腺癌发生中的可能作用，建立了在甲状腺球蛋白启动子(TG-Foxe1)作用下在甲状腺中高表达Foxe1的转基因小鼠。此外，TG-Foxe1小鼠在5周龄时接受X射线照射，或与Pten(+/-)小鼠杂交，分别检测Foxe1过表达与辐射或激活的磷脂酰肌醇-3-激酶/Akt通路的联合效应。在5-8周龄的TG-Foxe1小鼠中，观察到严重的甲状腺功能低下，小鼠的甲状腺实质发育不良。成年48周龄小鼠甲状腺功能减退基本恢复，甲状腺肿大，表现为胶样微囊和多个良性大滤泡-乳头状生长结节，未发现恶性病变。转基因小鼠暴露在1或8GyX射线和Pten单倍体不足促进了增生性结节的形成，也没有致癌作用。这些结果表明，Foxe1的过度表达并不直接参与甲状腺癌的发生发展，适当剂量的Foxe1对于获得正常的甲状腺结构和功能是必不可少的。
Recent genome-wide association studies have identified several single nucleotide polymorphisms in the forkhead box E1 gene (FOXE1) locus, which are strongly associated with the risk for thyroid cancer. In addition, our recent work has demonstrated FOXE1 overexpression in papillary thyroid carcinomas. To assess possible contribution of Foxe1 to thyroid carcinogenesis, transgenic mice overexpressing Foxe1 in their thyroids under thyroglobulin promoter (Tg-Foxe1) were generated. Additionally, Tg-Foxe1 mice were exposed to x-rays at the age of 5 weeks or crossed with Pten(+/-) mice to examine the combined effect of Foxe1 overexpression with radiation or activated phosphatidylinositol-3-kinase/Akt pathway, respectively. In 5- to 8-week-old Tg-Foxe1 mice, severe hypothyroidism was observed, and mouse thyroids exhibited hypoplasia of the parenchyma. Adult 48-week-old mice were almost recovered from hypothyroidism, their thyroids were enlarged, and featured colloid microcysts and multiple benign nodules of macrofollicular-papilloid growth pattern, but no malignancy was found. Exposure of transgenic mice to 1 or 8 Gy of x-rays and Pten haploinsufficiency promoted hyperplastic nodule formation also without carcinogenic effect. These results indicate that Foxe1 overexpression is not directly involved in the development of thyroid cancer and that proper Foxe1 dosage is essential for achieving normal structure and function of the thyroid.