RPB5-Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding
RPB5-Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding
复制标题
RPB5 介导蛋白通过与 NRF2 竞争 KEAP1 结合促进胆管癌肿瘤发生和耐药性
DOI：
10.1002/hep.30962
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发表时间：
2020-02-20
期刊：
影响因子：
13.5
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
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作者：
Wan, Zheng-Hua;Jiang, Tian-Yi;Wang, Hong-Yang
背景和目的癌细胞的存活取决于活性氧的产生和清除之间的平衡，而在肿瘤发生过程中，活性氧的产生和清除主要由NRF2调节。在这里，我们证明了在自主小鼠肝内胆管癌（ICC）模型中rbp5介导蛋白（RMP）的缺失可以延缓肿瘤的进展。方法和结果rmp过表达的肿瘤细胞对氧化应激和细胞凋亡的耐受性增强。机制上，RMP通过E**E基序与NRF2竞争结合KEAP1的Kelch结构域（Kelch样ECH-associated protein 1），通过泛素化导致NRF2降解减少，从而增加NRF2核易位和下游抗氧化基因的反激活。这个RMP-KEAP1-NRF2轴促进ICC的肿瘤发生、转移和耐药性。与这些发现一致，人ICC的RMP水平与NRF2蛋白水平呈正相关，并与不良预后相关。结论RMP参与氧化应激防御程序，可用于肿瘤靶向治疗。
Background and Aims Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5-mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression.Approach and Results RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch-like ECH-associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.Conclusion These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.