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Thyroid Hormone Receptor Beta Induces a Tumor-Suppressive Program in Anaplastic Thyroid Cancer.


ABSTRACT: The thyroid hormone receptor beta (TR?), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TR? is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TR? levels decreased tumor growth supporting the concept that TR? could function as a tumor suppressor. Yet, the TR? tumor suppression transcriptome is not well delineated and the impact of TR? is unknown in aggressive anaplastic thyroid cancer (ATC). Here, we establish that restoration of TR? expression in the human ATC cell line SW1736 (SW-TR?) reduces the aggressive phenotype, decreases cancer stem cell populations and induces cell death in a T3-dependent manner. Transcriptomic analysis of SW-TR? cells via RNA sequencing revealed distinctive expression patterns induced by ligand-bound TR? and revealed novel molecular signaling pathways. Of note, liganded TR? 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 TR?-driven tumor suppression transcriptomic signature, highlight unexplored therapeutic options for ATC, and support TR? activation as a promising therapeutic option in cancers. IMPLICATIONS: TR?-T3 induced a less aggressive phenotype and tumor suppression program in anaplastic thyroid cancer cells revealing new potential therapeutic targets.

SUBMITTER: Bolf EL 

PROVIDER: S-EPMC7541631 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Thyroid Hormone Receptor Beta Induces a Tumor-Suppressive Program in Anaplastic Thyroid Cancer.

Bolf Eric L EL   Gillis Noelle E NE   Davidson Cole D CD   Rodriguez Princess D PD   Cozzens Lauren L   Tomczak Jennifer A JA   Frietze Seth S   Carr Frances E FE  

Molecular cancer research : MCR 20200617 10


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 a  ...[more]

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