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Article: CRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress

TitleCRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress
Authors
KeywordsCCS
Drug resistance of hepatocellular carcinoma
In vivo CRISPR/Cas9 screen
MiR-3689a-3p
Sorafenib
Issue Date17-Nov-2023
PublisherElsevier
Citation
Drug Resistance Updates, 2023, v. 71 How to Cite?
Abstract

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 treatmentProteomic 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.


Persistent Identifierhttp://hdl.handle.net/10722/340977
ISSN
2023 Impact Factor: 15.8
2023 SCImago Journal Rankings: 4.665
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLu, Yuanjun-
dc.contributor.authorChan, Yau-Tuen-
dc.contributor.authorWu, Junyu-
dc.contributor.authorFeng, Zixin-
dc.contributor.authorYuan, Hongchao-
dc.contributor.authorLi, Qiucheng-
dc.contributor.authorXing, Tingyuan-
dc.contributor.authorXu, Lin-
dc.contributor.authorZhang, Cheng-
dc.contributor.authorTan, Hor-Yue-
dc.contributor.authorLee, Terence Kin-Wah-
dc.contributor.authorFeng, Yibin-
dc.contributor.authorWang, Ning-
dc.date.accessioned2024-03-11T10:48:45Z-
dc.date.available2024-03-11T10:48:45Z-
dc.date.issued2023-11-17-
dc.identifier.citationDrug Resistance Updates, 2023, v. 71-
dc.identifier.issn1368-7646-
dc.identifier.urihttp://hdl.handle.net/10722/340977-
dc.description.abstract<h3>Aims</h3><p>Therapeutic outcome of <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/sorafenib" title="Learn more about sorafenib from ScienceDirect's AI-generated Topic Pages">sorafenib</a> in <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/liver-cell-carcinoma" title="Learn more about hepatocellular carcinoma from ScienceDirect's AI-generated Topic Pages">hepatocellular carcinoma</a> (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/microrna" title="Learn more about microRNA from ScienceDirect's AI-generated Topic Pages">microRNA</a> (miRNA) which is responsible for sorafenib resistance at the genomic level.</p><h3>Methods</h3><p>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.</p><h3>Results</h3><p>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 <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/therapeutic-procedure" title="Learn more about treatment from ScienceDirect's AI-generated Topic Pages">treatment</a>. <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/proteomics" title="Learn more about Proteomic from ScienceDirect's AI-generated Topic Pages">Proteomic</a> analysis revealed that the effect of miR-3689a-3p was related to the copper-dependent mitochondrial <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/superoxide-dismutase" title="Learn more about superoxide dismutase from ScienceDirect's AI-generated Topic Pages">superoxide dismutase</a> 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 <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress" title="Learn more about oxidative stress from ScienceDirect's AI-generated Topic Pages">oxidative stress</a> 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.</p><h3>Conclusion</h3><p>Our findings provide comprehensive evidence for miR-3689a-3p as a positive regulator and potential druggable target for improving sorafenib treatment in HCC.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofDrug Resistance Updates-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCCS-
dc.subjectDrug resistance of hepatocellular carcinoma-
dc.subjectIn vivo CRISPR/Cas9 screen-
dc.subjectMiR-3689a-3p-
dc.subjectSorafenib-
dc.titleCRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.drup.2023.101015-
dc.identifier.scopuseid_2-s2.0-85175377963-
dc.identifier.volume71-
dc.identifier.eissn1532-2084-
dc.identifier.isiWOS:001106268300001-
dc.identifier.issnl1368-7646-

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