Inhibition of Tumorigenesis by the Thyroid Hormone Receptor β in Xenograft Models
Inhibition of Tumorigenesis by the Thyroid Hormone Receptor β in Xenograft Models
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DOI：
10.1089/thy.2013.0054
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发表时间：
2014-02-01
期刊：
影响因子：
6.6
通讯作者：
Cheng, Sheue-yann
中科院分区：
文献类型：
--
作者：
Kim, Won Gu;Zhao, Li;Cheng, Sheue-yann
背景：以往的研究表明，几种类型的人类癌症与甲状腺激素受体（TR）的体细胞突变和THRB基因的表观遗传失活和/或缺失导致的TR表达减少密切相关。这些观察结果表明，TR可能在癌变过程中发挥抑癌作用。然而，TR抑制肿瘤发生的机制尚不清楚。方法：利用人滤泡甲状腺癌细胞（FTC-133和FTC-236细胞），研究THRB基因的功能表达对肿瘤发生的影响。我们在FTC细胞中稳定表达THRB基因，并在基于细胞的研究和异种移植模型中评估了表达的TR对癌细胞增殖、迁移和肿瘤生长的影响。结果：在FTC-133细胞中，与不含TR的对照FTC细胞相比，TR的表达通过抑制AKT-mTOR-p70 S6K通路，降低了癌细胞的增殖，阻碍了肿瘤细胞的迁移。在异种移植物模型中，FTC-133和FTC-236中TR的表达导致肿瘤生长减少。重要的是，与不含TR的对照组FTC细胞相比，在表达TR的FTC细胞诱导的肿瘤中，新血管的形成明显受到抑制。血管形成的减少是由表达TR的FTC细胞中血管内皮生长因子的下调介导的。结论：这些发现表明，在FTC细胞中，TR通过下调AKT-mTOR-p70 S6K通路和降低血管内皮生长因子的表达来发挥肿瘤抑制作用。目前的结果表明，TR可能被认为是甲状腺癌的潜在治疗靶点。
Background: Previous studies showed a close association between several types of human cancers and somatic mutations of thyroid hormone receptor (TR) and reduced expression of TR due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TR could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TR could function to inhibit tumorigenesis are less well understood. Methods: We used the human follicular thyroid cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TR on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. Results: Expression of TR in FTC-133 cells, as compared with control FTC cells without TR, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT-mTOR-p70 S6K pathway. TR expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models. Importantly, new vessel formation was significantly suppressed in tumors induced by FTC cells expressing TR compared with control FTC cells without TR. The decrease in vessel formation was mediated by the downregulation of vascular endothelial growth factor in FTC cells expressing TR. Conclusions: These findings indicate that TR acts as a tumor suppressor through downregulation of the AKT-mTOR-p70 S6K pathway and decreased vascular endothelial growth factor expression in FTC cells. The present results raise the possibility that TR could be considered as a potential therapeutic target for thyroid cancer.