PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation
PAQR4 promotes chemoresistance in non-small cell lung cancer through inhibiting Nrf2 protein degradation
复制标题
PAQR4通过抑制Nrf2蛋白降解促进非小细胞肺癌化疗耐药
DOI：
10.7150/thno.43142
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Chen, Yongbin
中科院分区：
文献类型：
--
作者：
Xu, Peifang;Jiang, Liping;Chen, Yongbin
目的：肺癌是全球癌症相关死亡的主要原因。我们以前已经使用交叉值关联分析(CVAA)方法从大规模泛癌数据集中识别了许多差异表达基因(DEG)。本研究以位于高尔基体中的孕激素和ADIPOQ受体(PAQR)家族成员孕激素和AdipoQ受体4(PAQR4)为研究对象，探讨其在非小细胞肺癌(NSCLC)发生发展中的作用和机制。方法：采用组织芯片技术检测PAQR4的蛋白表达谱，观察PAQR4对非小细胞肺癌细胞增殖、集落形成和移植瘤形成的影响。结果：PAQR4在非小细胞肺癌(NSCLC)细胞系(A549、H1299、H1650、H1975、H358、GLC-82和SPC-A1)中表达增加，并在非小细胞肺癌(NSCLC)组织中检测到PAQR4的多种突变。我们证明了PAQR4的高表达与较差的临床结局相关，并且它的敲除通过诱导细胞凋亡来抑制细胞增殖。重要的是，在NSCLC细胞中，过表达的PAQR4与Nrf2在物理上相互作用，阻断了Nrf2与Keap1之间的相互作用。结论：我们的结果表明，PAQR4缺失可能通过Keap1介导的泛素化过程促进Nrf2蛋白的降解，从而增强肿瘤细胞在体外和体内对化疗的敏感性。
Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC).Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4.Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1.Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.