CRISPR/Cas9筛选揭示了miR-3689a-3p通过抑制CCS/SOD1依赖性线粒体氧化应激调节肝细胞癌中索拉非尼耐药性。

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Yuanjun Lu , Yau-Tuen Chan , Junyu Wu , Zixin Feng , Hongchao Yuan , Qiucheng Li , Tingyuan Xing , Lin Xu , Cheng Zhang , Hor-Yue Tan , Terence Kin-Wah Lee , Yibin Feng , Ning Wang
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引用次数: 0

摘要

目的:索拉非尼治疗肝细胞癌(HCC)的疗效因耐药性的发展而受到损害。本研究旨在从基因组水平鉴定引起索拉非尼耐药性的关键微小RNA(miRNA)。方法:应用CRISPR/Cas9筛选,然后在体外和体内进行功能获得和丧失分析,以确定miR-3689a-3p在HCC中介导索拉非尼反应中的作用。研究了miR-3689a-3p的上游和下游分子及其作用机制。结果:CRISPR/Cas9筛选发现miR-3689a-3p是索拉非尼敏感HCC中上调最多的miRNA。miR-3689a-3p的敲除显著增加了索拉非尼的耐药性,而其过表达使HCC对索拉非尼治疗的反应敏感。蛋白质组学分析表明,miR-3689a-3p的作用与铜依赖性线粒体超氧化物歧化酶1型(SOD1)活性有关。从机制上讲,miR-3689a-3p靶向超氧化物歧化酶(CCS)细胞内铜伴侣的3’UTR并抑制其表达。因此,miR-3689a-3p破坏了细胞内铜运输,并减少了SOD1介导的线粒体氧化应激清除,最终导致HCC细胞对索拉非尼治疗的死亡。CCS过度表达减弱了索拉非尼在HCC中的反应。临床上,miR-3689a-3p在HCC中下调,并预测HCC患者的良好预后。结论:我们的研究结果为miR-3689a-3p作为阳性调节因子和潜在的药物靶点改善索拉非尼治疗HCC提供了全面的证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress

Aims

Therapeutic outcome of sorafenib in hepatocellular carcinoma (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical microRNA (miRNA) which is responsible for sorafenib resistance at the genomic level.

Methods

CRISPR/Cas9 screen followed by gain- and loss-of-function assays both in vitro and in vivo were applied to identify the role of miR-3689a-3p in mediating sorafenib response in HCC. The upstream and downstream molecules of miR-3689a-3p and their mechanism of action were investigated.

Results

CRISPR/Cas9 screening identified miR-3689a-3p was the most up-regulated miRNA in sorafenib sensitive HCC. Knockdown of miR-3689a-3p significantly increased sorafenib resistance, while its overexpression sensitized HCC response to sorafenib treatment. Proteomic analysis revealed that the effect of miR-3689a-3p was related to the copper-dependent mitochondrial superoxide dismutase type 1 (SOD1) activity. Mechanistically, miR-3689a-3p targeted the 3′UTR of the intracellular copper chaperone for superoxide dismutase (CCS) and suppressed its expression. As a result, miR-3689a-3p disrupted the intracellular copper trafficking and reduced SOD1-mediated scavenge of mitochondrial oxidative stress that eventually caused HCC cell death in response to sorafenib treatment. CCS overexpression blunted sorafenib response in HCC. Clinically, miR-3689a-3p was down-regulated in HCC and predicted favorable prognosis for HCC patients.

Conclusion

Our findings provide comprehensive evidence for miR-3689a-3p as a positive regulator and potential druggable target for improving sorafenib treatment in HCC.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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