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THYROID HORMONE RECEPTOR BETA INDUCES A TUMOR SUPPRESSIVE PROGRAM IN ANAPLASTIC THYROID CANCER.
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2020-06-17 , DOI: 10.1158/1541-7786.mcr-20-0282
Eric L Bolf 1, 2 , Noelle E Gillis 1, 2 , Cole D Davidson 1, 2 , Princess D Rodriguez 3 , Lauren Cozzens 1 , Jennifer A Tomczak 1 , Seth Frietze 2, 3 , Frances E Carr 1, 2
Affiliation  

The thyroid hormone receptor beta (TRβ), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRβ is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TRβ levels decreased tumor growth supporting the concept that TRβ could function as a tumor suppressor. Yet, the TRβ tumor suppression transcriptome is not well delineated and the impact of TRβ is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TRβ expression in the human ATC cell line SW1736 (SW-TRβ) reduces the aggressive phenotype, decreases cancer stem cell populations and induces cell death in a T3-dependent manner. Transcriptomic analysis of SW-TRβ cells via RNA sequencing revealed distinctive expression patterns induced by ligand-bound TRβ and revealed novel molecular signaling pathways. Of note, liganded TRβ repressed multiple nodes in the PI3K/AKT pathway, induced expression of thyroid differentiation markers, and promoted proapoptotic pathways. Our results further revealed the JAK1–STAT1 pathway as a novel, T3-mediated, antitumorigenic pathway that can be activated in additional ATC lines. These findings elucidate a TRβ-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TRβ activation as a promising therapeutic option in cancers. Implications: TRβ-T3 induced a less aggressive phenotype and tumor suppression program in anaplastic thyroid cancer cells revealing new potential therapeutic targets.

中文翻译:

甲状腺激素受体 Beta 在甲状腺未分化癌中诱导肿瘤抑制程序。

甲状腺激素受体β(TRβ)是细胞生长和分化的关键调节因子,在癌症中经常失调。TRβ 的表达减少在甲状腺、乳腺癌和其他实体瘤中被发现,并且与更具侵袭性的疾病相关。TRβ水平的恢复减少了肿瘤生长,支持了TRβ可以作为肿瘤抑制因子的概念。然而,TRβ 肿瘤抑制转录组尚未得到很好的描述,并且 TRβ 在侵袭性甲状腺未变癌 (ATC) 中的影响尚不清楚。在这里,我们确定人 ATC 细胞系 SW1736 (SW-TRβ) 中 TRβ 表达的恢复会降低侵袭性表型,减少癌症干细胞群,并以 T3 依赖性方式诱导细胞死亡。通过 RNA 测序对 SW-TRβ 细胞进行转录组分析,揭示了配体结合的 TRβ 诱导的独特表达模式,并揭示了新的分子信号传导途径。值得注意的是,配体的 TRβ 抑制 PI3K/AKT 通路中的多个节点,诱导甲状腺分化标志物的表达,并促进促凋亡通路。我们的结果进一步揭示了 JAK1-STAT1 途径是一种新型的、T3 介导的抗肿瘤发生途径,可以在其他 ATC 系中激活。这些发现阐明了 TRβ 驱动的肿瘤抑制转录组特征,突出了 ATC 尚未探索的治疗选择,并支持 TRβ 激活作为癌症的一种有前途的治疗选择。意义:TRβ-T3 在未分化甲状腺癌细胞中诱导了一种侵袭性较低的表型和肿瘤抑制程序,揭示了新的潜在治疗靶点。
更新日期:2020-06-17
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