甲状旁腺素受体α1（TRα1）介导着甲状旁腺素（T3）的基因组作用。关于TRα1在生长和发育中的生物学研究已有充分的探究，但TRα1在癌症中的功能角色尚待阐明。分析癌症基因组图谱（TCGA）的人类甲状腺癌数据库显示，高度分化的间叶性甲状腺癌（ATC）中THRA基因表达丧失。因此，我们探究了TRα1对ATC进展的影响。我们在两个人类ATC细胞系（THJ-11T和THJ-16T）中稳定表达了TRα1（11T-TRα1 ＃2，＃7和＃8，以及16T-TRα1 ＃3，＃4和＃8）。我们发现，表达的TRα1抑制了ATC细胞的增殖并诱导了凋亡。TCGA数据显示，THRA基因表达与配盒基因8（PAX8）最为相关。一致地，我们发现，在父代11T和16T细胞中，PAX8表达几乎不可检测。然而，在11T-和16T-TRα1表达细胞中，PAX8基因表达在mRNA和蛋白质水平上升。通过各种分子分析，我们发现TRα1直接调控了PAX8基因的表达。单细胞转录组分析（scRNA-seq）证明TRα1通过多个信号通路作为转录因子发挥作用，抑制肿瘤生长。重要的是，scRNA-seq分析显示，TRα1通过其转录程序诱导PAX8，将ATC的细胞景观转向分化状态。本研究表明TRα1是甲状腺分化的新鉴定调节因子，并可作为改善ATC患者预后的潜在治疗靶点。© 2023. 这是一项美国政府工作，并不受美国版权保护；可能适用外国版权保护。

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.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.