Abstract：
The THRA gene, encoding the thyroid hormone nuclear receptor TRα1, is expressed in an increasing gradient at the bottom of intestinal crypts, overlapping with high Wnt and Notch activities. Importantly, THRA is upregulated in colorectal cancers, particularly in the high-Wnt molecular subtype. The basis of this specific and/or altered expression pattern has remained unknown. To define the mechanisms controlling THRA transcription and TRα1 expression, we used multiple in vitro and ex vivo approaches. Promoter analysis demonstrated that transcription factors important for crypt homeostasis and altered in colorectal cancers, such as transcription factor 7-like 2 (TCF7L2; Wnt pathway), recombining binding protein suppressor of hairless (RBPJ; Notch pathway), and homeobox protein CDX2 (epithelial cell identity), modulate THRA activity. Specifically, although TCF7L2 and CDX2 stimulated THRA, RBPJ induced its repression. In-depth analysis of the Wnt-dependent increase showed direct regulation of the THRA promoter in cells and of TRα1 expression in murine enteroids. Given our previous results on the control of the Wnt pathway by TRα1, our new results unveil a complex regulatory loop and synergy between these endocrine and epithelial-cell-intrinsic signals. Our work describes, for the first time, the regulation of the THRA gene in specific cell and tumor contexts.
摘要：
THRA基因,编码甲状腺激素核受体TRα1，在肠隐窝底部以增加的梯度表达，与高Wnt和Notch活性重叠。重要的是,THRA在结直肠癌中上调，特别是在高Wnt分子亚型中。这种特异性和/或改变的表达模式的基础仍然未知。为了确定控制THRA转录和TRα1表达的机制，我们使用了多种体外和离体方法。启动子分析表明，在结直肠癌中对隐窝稳态和改变很重要的转录因子，如转录因子7样2（TCF7L2;Wnt通路），重组无毛结合蛋白抑制因子（RBPJ；Notch通路），和同源异型盒蛋白CDX2（上皮细胞身份），调节THRA活性。具体来说,尽管TCF7L2和CDX2刺激了THRA，RBPJ诱导其抑制。对Wnt依赖性增加的深入分析显示了细胞中THRA启动子和鼠类肠样物质中TRa1表达的直接调节。鉴于我们先前关于TRα1控制Wnt途径的结果，我们的新结果揭示了这些内分泌和上皮细胞固有信号之间的复杂调节环和协同作用。我们的工作描述，第一次,THRA基因在特定细胞和肿瘤环境中的调控。
