Tran Tuyen Thanh, Lee Keesook
Laboratory of Developmental Genetics, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea.
Cancers (Basel). 2022 Apr 10;14(8):1911. doi: 10.3390/cancers14081911.
The pro-oncogenic function of TR3, an orphan nuclear receptor, has been reported in prostate cancer. However, the roles of TR3 in androgen receptor (AR) expression and signaling in prostate cancer cells are poorly understood. Database analysis revealed that TR3 expression level is elevated in prostate tumors, and is positively, although weakly, correlated with that of AR. TR3 overexpression increased the production of AR splice variants in addition to general upregulation of AR expression. TR3 interacted with some spliceosomal complex components and AR precursor mRNA, altering the splice junction rates between exons. TR3 also enhanced androgen-independent AR function. Furthermore, TR3 overexpression increased cell proliferation and mobility of AR-positive prostate cancer cells and stimulated tumorigenesis of androgen-independent prostate cancer cells in mouse xenograft models. This is the first study to report that TR3 is a multifunctional regulator of AR signaling in prostate cancer cells. TR3 alters AR expression, splicing process, and activity in prostate cancer cells, increasing the androgen independence of AR signaling. Therefore, TR3 may play a crucial role in the progression of prostate cancer to an advanced castration-resistant form.
孤儿核受体TR3的促癌功能已在前列腺癌中被报道。然而，TR3在前列腺癌细胞中雄激素受体（AR）表达及信号传导方面的作用仍知之甚少。数据库分析显示，TR3在前列腺肿瘤中的表达水平升高，且与AR的表达呈正相关，尽管相关性较弱。TR3过表达除了使AR表达普遍上调外，还增加了AR剪接变体的产生。TR3与一些剪接体复合物成分及AR前体mRNA相互作用，改变了外显子之间的剪接连接率。TR3还增强了雄激素非依赖性AR功能。此外，在小鼠异种移植模型中，TR3过表达增加了AR阳性前列腺癌细胞的增殖和迁移能力，并刺激了雄激素非依赖性前列腺癌细胞的肿瘤发生。这是首次报道TR3是前列腺癌细胞中AR信号的多功能调节因子的研究。TR3改变前列腺癌细胞中AR的表达、剪接过程和活性，增加AR信号的雄激素非依赖性。因此，TR3可能在前列腺癌进展为晚期去势抵抗性形式中起关键作用。
