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Article: NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma

TitleNRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma
Authors
KeywordsDrug resistance
Hepatocellular carcinoma
Sonic hedgehog
Sorafenib
Tumor initiating cells
Issue Date2020
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/canlet
Citation
Cancer Letters, 2020, v. 476, p. 48-56 How to Cite?
AbstractSolid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which lead to a poor prognosis in patients with hepatocellular carcinoma (HCC). Through an in vitro liver T-IC enrichment approach, we identified nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a transcription regulator that is significantly activated in enriched liver T-IC populations. In human HCCs, NRF2 was found to be overexpressed, which was associated with poor patient survival. Through a lentiviral based knockdown approach, NRF2 was found to be critical for regulating liver T-IC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver T-IC markers. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance in HCC cells. Mechanistically, NRF2 was found to physically bind to the promoter of sonic hedgehog homolog (SHH), which triggers activation of the sonic hedgehog pathway. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated T-IC function via upregulation of SHH expression. Our study suggests a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through the NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes.
Persistent Identifierhttp://hdl.handle.net/10722/281866
ISSN
2019 Impact Factor: 7.36
2015 SCImago Journal Rankings: 2.331
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLeung, HW-
dc.contributor.authorLau, EYT-
dc.contributor.authorLeung, CON-
dc.contributor.authorLei, MML-
dc.contributor.authorMok, EHK-
dc.contributor.authorMa, VWS-
dc.contributor.authorCho, WCS-
dc.contributor.authorNg, IOL-
dc.contributor.authorYun, JP-
dc.contributor.authorCai, SH-
dc.contributor.authorMa, S-
dc.contributor.authorLee, TK-
dc.date.accessioned2020-04-03T07:22:53Z-
dc.date.available2020-04-03T07:22:53Z-
dc.date.issued2020-
dc.identifier.citationCancer Letters, 2020, v. 476, p. 48-56-
dc.identifier.issn0304-3835-
dc.identifier.urihttp://hdl.handle.net/10722/281866-
dc.description.abstractSolid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which lead to a poor prognosis in patients with hepatocellular carcinoma (HCC). Through an in vitro liver T-IC enrichment approach, we identified nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a transcription regulator that is significantly activated in enriched liver T-IC populations. In human HCCs, NRF2 was found to be overexpressed, which was associated with poor patient survival. Through a lentiviral based knockdown approach, NRF2 was found to be critical for regulating liver T-IC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver T-IC markers. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance in HCC cells. Mechanistically, NRF2 was found to physically bind to the promoter of sonic hedgehog homolog (SHH), which triggers activation of the sonic hedgehog pathway. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated T-IC function via upregulation of SHH expression. Our study suggests a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through the NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes.-
dc.languageeng-
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/canlet-
dc.relation.ispartofCancer Letters-
dc.subjectDrug resistance-
dc.subjectHepatocellular carcinoma-
dc.subjectSonic hedgehog-
dc.subjectSorafenib-
dc.subjectTumor initiating cells-
dc.titleNRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailMa, S: stefma@hku.hk-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityMa, S=rp00506-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.canlet.2020.02.008-
dc.identifier.pmid32061952-
dc.identifier.scopuseid_2-s2.0-85079374793-
dc.identifier.hkuros309605-
dc.identifier.volume476-
dc.identifier.spage48-
dc.identifier.epage56-
dc.identifier.isiWOS:000525867300005-
dc.publisher.placeIreland-
dc.identifier.issnl0304-3835-

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