TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
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DOI：
10.1016/j.ebiom.2019.06.046
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发表时间：
2019-07-01
期刊：
影响因子：
11.1
通讯作者：
Landstrom, Marene
中科院分区：
文献类型：
--
作者：
Aripaka, Karthik;Gudey, Shyam Kumar;Landstrom, Marene
背景：肿瘤坏死因子受体相关因子6 （TRAF6）在多种细胞因子的作用下促进炎症反应。异常的Wnt3a信号通过β -连环蛋白的积累促进癌症进展。在这里，我们研究了TRAF6在Wnt信号传导中的潜在作用。方法：用siRNA在人前列腺癌（PC3U）和人结直肠癌SW480细胞中沉默TRAF6表达，用CRISPR/Cas9在斑马鱼中沉默TRAF6表达。利用几种生化方法和斑马鱼突变表型分析，分析了TRAF6在Wnt信号传导中的作用。研究结果：wnt3a处理促进了体外PC3U和LNCaP细胞中TRAF6与Wnt共受体LRP5/LRP6的结合。TRAF6正调控PC3U细胞中β - catenin mRNA的表达和Wnt靶基因的激活。当TRAF6被siRNA沉默后，wnt3a诱导的PC3U和SW480细胞的侵袭明显减少。数据库分析显示前列腺癌患者中TRAF6 mRNA与Wnt靶基因存在相关性，LRP5、TRAF6和c-Myc高表达与预后不良相关。我们利用CRISPR/Cas9在斑马鱼中沉默TRAF6，证实了TRAF6是Wnt3a信号通路中表达Wnt靶基因的关键分子。解释：我们发现TRAF6是wnt3a信号传导中的一个重要组成部分，可以促进Wnt靶基因的激活，这一发现对于理解驱动前列腺癌进展的机制很重要。(C) 2019作者。Elsevier B.V.出版
Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of beta-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of beta-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.Interpretation: We identify TRAF6 as an important component inWnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression. (C) 2019 The Author(s). Published by Elsevier B.V.