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Article: Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma

TitleEpigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma
Authors
KeywordsMiR-23a-3p
Sorafenib resistance
ETS1
Ferroptosis
ACSL4
Issue Date2022
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.jeccr.com/home
Citation
Journal of Experimental and Clinical Cancer Research, 2022, v. 41, p. article no. 3 How to Cite?
AbstractBackground: Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods: The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results: We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion: Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.
Persistent Identifierhttp://hdl.handle.net/10722/309907
ISSN
2023 Impact Factor: 11.4
2023 SCImago Journal Rankings: 2.806
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLU, Y-
dc.contributor.authorChan, YT-
dc.contributor.authorTan, HY-
dc.contributor.authorZHANG, C-
dc.contributor.authorGUO, W-
dc.contributor.authorXu, Y-
dc.contributor.authorSharma, R-
dc.contributor.authorChen, ZS-
dc.contributor.authorZheng, YC-
dc.contributor.authorWang, N-
dc.contributor.authorFeng, Y-
dc.date.accessioned2022-01-10T09:15:36Z-
dc.date.available2022-01-10T09:15:36Z-
dc.date.issued2022-
dc.identifier.citationJournal of Experimental and Clinical Cancer Research, 2022, v. 41, p. article no. 3-
dc.identifier.issn1756-9966-
dc.identifier.urihttp://hdl.handle.net/10722/309907-
dc.description.abstractBackground: Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods: The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results: We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion: Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.jeccr.com/home-
dc.relation.ispartofJournal of Experimental and Clinical Cancer Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectMiR-23a-3p-
dc.subjectSorafenib resistance-
dc.subjectETS1-
dc.subjectFerroptosis-
dc.subjectACSL4-
dc.titleEpigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailXu, Y: xyzjh@HKUCC-COM.hku.hk-
dc.identifier.emailSharma, R: rasharma@hku.hk-
dc.identifier.emailWang, N: ckwang@hku.hk-
dc.identifier.emailFeng, Y: yfeng@hku.hk-
dc.identifier.authorityWang, N=rp02075-
dc.identifier.authorityFeng, Y=rp00466-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s13046-021-02208-x-
dc.identifier.pmid34980204-
dc.identifier.pmcidPMC8722264-
dc.identifier.scopuseid_2-s2.0-85122216248-
dc.identifier.hkuros331408-
dc.identifier.volume41-
dc.identifier.spagearticle no. 3-
dc.identifier.epagearticle no. 3-
dc.identifier.isiWOS:000738031400004-
dc.publisher.placeUnited Kingdom-

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