Hypoxia-induced Nur77 activates PI3K/Akt signaling via suppression of Dicer/let-7i-5p to induce epithelial-to-mesenchymal transition.
Hypoxia-induced Nur77 activates PI3K/Akt signaling via suppression of Dicer/let-7i-5p to induce epithelial-to-mesenchymal transition.
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缺氧诱导的 Nur77 通过抑制 Dicer/let-7i-5p 激活 PI3K/Akt 信号传导，诱导上皮间质转化
DOI：
10.7150/thno.52190
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Wong AST
中科院分区：
文献类型：
--
作者：
Shi Z;To SKY;Zhang S;Deng S;Artemenko M;Zhang M;Tang J;Zeng JZ;Wong AST
背景：大肠癌（CRC）和相关的转移性病变被报道是缺氧的。缺氧是肿瘤微环境中的一个共同特征，也是CRC的一个强有力的刺激因素。我们已经确定了Nur 77对Akt活化的调节作用，以增强缺氧条件下CRC进展所必需的β-连环蛋白信号传导。研究方法：Nur 77在低氧诱导的EMT中的功能作用通过散射测定来检查，以监测CRC细胞系在1%O2下的形态。进行球体形成测定以研究Nur 77是否在缺氧CRC细胞中诱导癌症干细胞样性质。通过qPCR和蛋白质印迹分析各种上皮-间充质转化（EMT）和干性标志物的表达。最后，使用用适当构建体稳定转染的CRC细胞，在裸鼠的皮下肿瘤异种移植物或肝转移模型中确定Nur 77体内功能和信号传导。结果如下：在本文中，我们首次表明Nur 77是microRNA生物合成的新型调节剂，这可能是其在缺氧条件下在CRC细胞中显着的促肿瘤活性的基础。Nur 77与抑癌蛋白p63相互作用，抑制了Dicer（一种重要的miRNA加工蛋白）的p63依赖性转录，降低了let-7i-5 p（靶向p110α mRNA的3 'UTR并调节其稳定性）的生物合成。Nur 77的敲低或let-7i-5 p的过表达抑制了体内肿瘤转移。结论：我们的数据揭示了连接Nur 77，Akt和CRC在缺氧微环境中的侵袭性的新机制。
Background: Colorectal cancer (CRC) and the associated metastatic lesions are reported to be hypoxic. Hypoxia is a common feature in the tumor microenvironment and a potent stimulant of CRC. We have identified a regulatory role of Nur77 on Akt activation to enhance β-catenin signaling essential for CRC progression under hypoxic conditions. Methods: The functional role of Nur77 in hypoxia-induced EMT was examined by scattering assays to monitor the morphologies of CRC cell lines under 1% O2. Sphere formation assays were performed to investigate whether Nur77 induced cancer stem cell-like properties in hypoxic CRC cells. The expression of various epithelial-to-mesenchymal transition (EMT) and stemness markers was analyzed by qPCR and Western blotting. Finally, Nur77 function and signaling in vivo was ascertained in subcutaneous tumor xenograft or liver metastasis model in nude mice using CRC cells stably transfected with appropriate constructs. Results: Herein, we show, for the first time, that Nur77 is a novel regulator of microRNA biogenesis that may underlie its significant tumor-promoting activities in CRC cells under hypoxia. Mechanistically, Nur77 interacted with the tumor suppressor protein p63, leading to the inhibition of p63-dependent transcription of Dicer, an important miRNA processor and subsequent decrease in the biogenesis of let-7i-5p which targeted the 3'UTR of p110α mRNA and regulated its stability. Knockdown of Nur77 or overexpression of let-7i-5p inhibited the tumor metastasis in vivo. Conclusion: Our data uncovered a novel mechanistic link connecting Nur77, Akt, and invasive properties of CRC in the hypoxic microenvironment.
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