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Thyroid hormone receptor α1: a novel regulator of thyroid cancer cell differentiation

Oncogene volume 42, pages 3075–3086 (2023)Cite this article

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Abstract

Thyroid hormone receptor α1 (TRα1) mediates the genomic actions of thyroid hormone (T3). The biology of TRα1 in growth and development has been well studied, but the functional role of TRα1 in cancers remains to be elucidated. Analysis of the human thyroid cancer database of The Cancer Genome Atlas (TCGA) showed that THRA gene expression is lost in highly dedifferentiated anaplastic thyroid cancer (ATC). We, therefore, explored the effects of TRα1 on the progression of ATC. We stably expressed TRα1 in two human ATC cell lines, THJ-11T (11T-TRα1 #2, #7, and #8) and THJ-16T (16T-TRα1 #3, #4, and #8) cells. We found that the expressed TRα1 inhibited ATC cell proliferation and induced apoptosis. TCGA data showed that THRA gene expression was best correlated with the paired box gene 8 (PAX8). Consistently, we found that the PAX8 expression was barely detectable in parental 11T and 16T cells. However, PAX8 gene expression was elevated in 11T- and 16T-TRα1-expressing cells at the mRNA and protein levels. Using various molecular analyses, we found that TRα1 directly regulated the expression of the PAX8 gene. Single-cell transcriptomic analyses (scRNA-seq) demonstrated that TRα1 functions as a transcription factor through multiple signaling pathways to suppress tumor growth. Importantly, scRNA-seq analysis showed that TRα1-induced PAX8, via its transcription program, shifts the cell landscape of ATC toward a differentiated state. The present studies suggest that TRα1 is a newly identified regulator of thyroid differentiation and could be considered as a potential therapeutic target to improve the outcome of ATC patients.

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Fig. 1: TRα1 inhibits cell growth of ATC cells.
Fig. 2: TRα1 suppresses xenograft tumor growth induced by ATC cells.
Fig. 3: TRα1 suppresses xenograft tumor growth by decreasing proliferation and induction of apoptosis.
Fig. 4: Close relationship between THRA and PAX8 gene for differentiation of human thyroid cancer.
Fig. 5: TRα1 enhances PAX8 expression in ATC-cultured cells and xenograft tumors.
Fig. 6: TRα1 directly regulates the expression of the PAX8 gene.
Fig. 7: scRNA-seq shows that TRα1-activated PAX8 re-differentiates ATC tumors.
Fig. 8: TRα1 increases the NIS protein levels in ATC-cultured cells and xenograft tumors.

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Data availability

scRNA-seq data have been submitted to NCBI GEO. The GEO accession number is GSE235216 for accessing the data.

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Acknowledgements

This research was supported by the Intramural Research Programs of the Center for Cancer Research of the National Cancer Institute, National Institutes of Health. We thank Dr. Michael Kelly and his team for carrying out single-cell RNA sequencing at the Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory (Leidos Biomed), NCI. We also thank Joelle Mornini, NIH Library, for manuscript editing assistance.

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  1. Woo Kyung Lee Doolittle

    Present address: Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, 44106, USA

Authors and Affiliations

  1. Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Eunmi Hwang, Woo Kyung Lee Doolittle, Xuguang Zhu, Li Zhao & Sheue-yann Cheng

  2. Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Yuelin Jack Zhu & Yanlin Yu

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Contributions

Conception and designs were performed by S-YC, EH, WKLD, YJZ and XZ. Development of methodology and acquisition of data were carried out by EH, WKLD, YJZ, XZ, LZ, and YY. Analysis and interpretation of data were performed by EH, WKLD, YJZ, XZ, YY and S-YC. Administrative, technical, or material support were performed by S-YC and LZ.

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Correspondence to Sheue-yann Cheng.

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Hwang, E., Doolittle, W.K.L., Zhu, Y.J. et al. Thyroid hormone receptor α1: a novel regulator of thyroid cancer cell differentiation. Oncogene 42, 3075–3086 (2023). https://doi.org/10.1038/s41388-023-02815-2

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