Wang Wen-Ling, Hong Guan-Ci, Chien Peng-Ju, Huang Yu-Hao, Lee Hsueh-Te, Wang Po-Hui, Lee Yueh-Chun, Chang Wen-Wei
School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.
Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 11221, Taiwan.
Cancers (Basel). 2020 Dec 15;12(12):3785. doi: 10.3390/cancers12123785.
Endometrial cancer (EC) is the second most common gynecological malignancy worldwide. Tribbles pseudokinase 3 (TRIB3) is a scaffolding protein that regulates intracellular signal transduction, and its role in tumor development is controversial. Here, we investigated the biological function of TRIB3 in EC. We found that the messenger RNA (mRNA) expression level of TRIB3 was significantly and positively correlated with shorter overall survival of EC patients in The Cancer Genome Atlas database. The protein expression of TRIB3 was found to be significantly increased in EC cancer stem cells (CSCs) enriched by tumorsphere cultivation. Knockdown of TRIB3 in EC cells suppressed tumorsphere formation, the expression of cancer stemness genes, and the in vivo tumorigenesis. The expression of β-catenin at both the protein and the mRNA levels was downregulated upon TRIB3 silencing. TRIB3 was found to interact with E74 Like ETS transcription factor 4 (ELF4) in the nucleus and bound to ELF4 consensus sites within the catenin beta 1 () promoter in EC cell lines. These data indicated that TRIB3 may regulate transcription by enhancing the recruitment of ELF4 to the promoter. In conclusion, our results suggest that TRIB3 plays an oncogenic role in EC and positively regulates the self-renewal and tumorigenicity of EC-CSCs. Targeting TRIB3 is considered as a potential therapeutic strategy in future EC therapy.
子宫内膜癌（EC）是全球第二常见的妇科恶性肿瘤。 Tribbles假激酶3（TRIB3）是一种调节细胞内信号转导的支架蛋白，其在肿瘤发生发展中的作用存在争议。在此，我们研究了TRIB3在EC中的生物学功能。我们发现在癌症基因组图谱数据库中，TRIB3的信使核糖核酸（mRNA）表达水平与EC患者较短的总生存期显著正相关。通过肿瘤球培养富集的EC癌症干细胞（CSCs）中，TRIB3的蛋白表达显著增加。在EC细胞中敲低TRIB3可抑制肿瘤球形成、癌症干性基因的表达以及体内肿瘤发生。TRIB3沉默后，β-连环蛋白在蛋白和mRNA水平的表达均下调。在细胞核中，TRIB3被发现与E74样ETS转录因子4（ELF4）相互作用，并在EC细胞系中与连环蛋白β1（）启动子内的ELF4共有位点结合。这些数据表明，TRIB3可能通过增强ELF4对启动子的募集来调节转录。总之，我们的结果表明TRIB3在EC中发挥致癌作用，并正向调节EC-CSCs的自我更新和致瘤性。靶向TRIB3被认为是未来EC治疗的一种潜在治疗策略。
