Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis.
Bile acids regulate nuclear receptor (Nur77) expression and intracellular location to control proliferation and apoptosis.
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DOI：
10.1158/1541-7786.mcr-14-0230
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Wan YJ
中科院分区：
文献类型：
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作者：
Hu Y;Chau T;Liu HX;Liao D;Keane R;Nie Y;Yang H;Wan YJ
胆汁酸（BA）是能够在整个胃肠道（GI）中引起癌症的内源性物质。为了揭示BA发挥致癌作用的机制，用BA处理人肝癌和结肠癌细胞以及小鼠原代肝细胞，并测定活力、遗传毒性应激和转录反应。BA诱导Nur 77（NR 4A 1）和促炎基因表达。BA诱导的Nur 77的细胞内定位是时间依赖性的;短期（1-3小时）暴露诱导核Nur 77，而较长时间（1-2天）暴露也增加了胞质Nur 77的表达和凋亡。用来普霉素B抑制Nur 77细胞核输出可减少LCA诱导的细胞凋亡。延长（7天）处理BA产生的电阻BA与增加核Nur 77，活力和流动性。同时，在BA抗性细胞中敲低Nur 77增加了细胞对LCA诱导的凋亡的敏感性。此外，体内小鼠异种移植物实验表明，与亲本对照相比，BA抗性细胞形成具有升高的Nur 77表达的较大肿瘤。DNA结合和基因表达测定鉴定了多种存活基因（CDK 4、CCND 2、MAP 4K 5、STAT 5A和RBBP 8）和促凋亡基因（BID）作为Nur 77靶点。一致地，BA诱导的上述基因的上调因Nur 77的缺乏而被废除。重要的是，Nur 77在高百分比的人结肠癌和肝癌样本中过表达，并且Nur 77的细胞内定位与结肠癌患者中升高的血清总BA水平相关。这些数据首次表明，BAs通过Nur 77在调节细胞存活和死亡方面具有双重作用。这些发现建立了Nur 77和胆汁酸致癌作用之间的直接联系。
Bile acids (BAs) are endogenous agents capable of causing cancer throughout the gastrointestinal (GI) tract. To uncover the mechanism by which BAs exert carcinogenic effects, both human liver and colon cancer cells as well as mouse primary hepatocytes were treated with BAs and assayed for viability, genotoxic stress, and transcriptional response. BAs induced both Nur77 (NR4A1) and pro-inflammatory gene expression. The intracellular location of BA-induced Nur77 was time-dependent; short-term (1–3 h) exposure induced nuclear Nur77 whereas longer (1–2 days) exposure also increased cytosolic Nur77 expression and apoptosis. Inhibiting Nur77 nuclear export with leptomycin B decreased LCA-induced apoptosis. Extended (7 days) treatment with BA generated resistance to BA with increased nuclear Nur77, viability, and mobility. While, knockdown of Nur77 in BA-resistant cells increased cellular susceptibility to LCA-induced apoptosis. Moreover, in vivo mouse xenograft experiments demonstrated that BA-resistant cells form larger tumors with elevated Nur77 expression compared to parental controls. DNA-binding and gene expression assays identified multiple survival genes (CDK4, CCND2, MAP4K5, STAT5A, and RBBP8) and a pro-apoptosis gene (BID) as Nur77 targets. Consistently, BA-induced up-regulation of the aforementioned genes was abrogated by a lack of Nur77. Importantly, Nur77 was overexpressed in high percentage of human colon and liver cancer specimens and the intracellular location of Nur77 correlated with elevated serum total BA levels in colon cancer patients. These data show for the first time that BAs via Nur77 have a dual role in modulating cell survival and death. Implications: These findings establish a direct link between Nur77 and the carcinogenic effect of bile acids.