Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor
Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor
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DOI：
10.3390/cancers10120520
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发表时间：
2018-12-01
期刊：
影响因子：
5.2
通讯作者：
Zhang, Yiguo
中科院分区：
文献类型：
--
作者：
Qiu, Lu;Wang, Meng;Zhang, Yiguo
小鼠肝脏特异性敲除Nrf1可导致自发性发展为非酒精性脂肪性肝炎伴血脂异常，然后其恶化导致肝癌，但其潜在机制尚不清楚。本文使用人类Nrf1 α特异性敲除细胞系重建了类似的病理模型。我们的证据表明，炎症标志物COX2的显著增加肯定发生在Nrf1 α(-/-)细胞中。Nrf1 α的缺失导致Nrf2的过度激活，这是由于Nrf1 α(-/-)细胞中Keap1、PTEN和大多数26S蛋白酶体亚基的大量减少。对异种移植模型小鼠的进一步研究表明，Nrf2沉默几乎可以消除Nrf1 α(-/-)衍生肿瘤的恶性生长，而Nrf1 α(+/+)-肿瘤被非活性突变体(即Nrf2（-/-)(Delta TA)）显著抑制，但在很大程度上不受先天构成激活剂（即caNrf2(Delta N)）的影响。机制研究结合转录组测序，揭示了Nrf1 α和Nrf2在内源性调控网络的不同层次上从多个信号传导到靶基因的差异表达谱的对立和统一的调控间交叉对话的全景。总的来说，Nrf1 α通过限制Nrf2的致癌性表现出显性的肿瘤抑制作用。Nrf2作为肿瘤启动子，也可以反过来直接激活Nrf1的转录表达，形成负反馈循环。鉴于Nrf1 α之间的相互调控。因此，在解释Nrf1 α、Nrf2或两者同时缺失的实验结果时，应非常谨慎。
Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of nonalcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1 alpha-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1 alpha(-/-) cells. Loss of Nrf1 alpha leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1 alpha(-/-) cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1 alpha(-/-)-derived tumors is almost abolished by silencing of Nrf2, while Nrf1 alpha(+/+)-tumor is markedly repressed by an inactive mutant (i.e., Nrf2(-/-)(Delta TA)) , but largely unaffected by a priori constitutive activator (i.e., caNrf2(Delta N)). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1 alpha and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1 alpha manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity. Though as a tumor promoter, Nrf2 can also, in turn, directly activate the transcriptional expression of Nrf1 to form a negative feedback loop. In view of such mutual inter-regulation by between Nrf1 alpha. and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1 alpha, Nrf2 or both.