FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells
FOXO3a modulates WNT/β-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells
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FOXO3a 调节 WNT/β-连环蛋白信号传导并抑制前列腺癌细胞的上皮间质转化
DOI：
10.1016/j.cellsig.2015.01.001
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发表时间：
2015-03-01
影响因子：
4.8
通讯作者：
He, Zhimin
中科院分区：
文献类型：
--
作者：
Liu, Hao;Yin, Jiang;He, Zhimin
新出现的证据表明，叉头框O（FOXO）的表达与前列腺癌的分级和扩散呈负相关，这表明其作为前列腺癌转移抑制因子的作用。然而，对于FOX转录因子在前列腺癌进展中的作用仍不完全了解。在本研究中，我们证明FOXO3a显著抑制前列腺癌细胞中p -连环蛋白的表达。抑制p -连环蛋白表达的机制涉及FOXO3a介导的微小RNA - 34b/c的转录激活，其通过靶向p -连环蛋白的非翻译区（UTRs）从而抑制p -连环蛋白的mRNA表达。此外，FOXO3a可直接与p -连环蛋白结合，并与TCF竞争与p -连环蛋白的相互作用，从而抑制β -连环蛋白/TCF转录活性并降低p -连环蛋白靶基因的表达。此外，表达FOXO3a shRNAs的前列腺癌细胞呈现间充质特性，包括细胞迁移增强以及上皮 - 间质转化（EMT）标志物的差异调节，而p -连环蛋白的敲低导致FOXO3a介导的EMT表型变化的逆转。总之，这些观察结果表明，FOXO3a抑制依赖于p -连环蛋白对EMT相关基因的调节的恶性表型，并为FOXO3a - miR - 34b/c轴在前列腺癌细胞中抑制经典的p -连环蛋白信号级联的机制提供了新的见解。（C）2015爱思唯尔公司。保留所有权利。
Emerging evidence has revealed a negative correlation between Forkhead box-O (FOXO) expression and prostate cancer grade and spread, indicating its role as a suppressor of prostate cancer metastasis. However, there is still incomplete understanding about the role of FOX transcription factors in prostate cancer progression. In this investigation, we demonstrate that FOXO3a significantly inhibits the expression p-catenin in prostate cancer cells. The mechanism of inhibiting p-catenin expression involves the FOXO3a-mediated transactivated microRNA-34b/c, which consequently suppressed p-catenin mRNA expression by targeting the untranslated regions (UTRs) of p-catenin. Additionally, FOXO3a can directly bind to p-catenin, and competes with TCF for interaction with p-catenin, thereby inhibiting beta-catenin/TCF transcriptional activity and reducing the expression of p-catenin target genes. Furthermore, prostate cancer cells expressing FOXO3a shRNAs display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers, whereas knockdown of p-catenin results in reversal of FOXO3a-mediated EMT phenotypic changes. Collectively, these observations demonstrated that FOXO3a inhibits malignant phenotypes that are dependent on p-catenin-dependent modulation of EMT-related genes, and provided fresh insight into the mechanisms by which a FOXO3a-miR-34b/c axis restrains canonical p-catenin signaling cascades in prostate cancer cell. (C) 2015 Elsevier Inc All rights reserved.