Association of NRF2 with HIF-2α-induced cancer stem cell phenotypes in chronic hypoxic condition.
Humans
NF-E2-Related Factor 2
/ genetics
Hypoxia
/ metabolism
Cell Hypoxia
/ genetics
MicroRNAs
/ genetics
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Neoplastic Stem Cells
/ metabolism
Colorectal Neoplasms
/ metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Tumor Microenvironment
Cancer stem cell phenotype
Chronic hypoxia
HIF-2α
NRF2
miR-181a-2-3p
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
13
01
2023
revised:
06
02
2023
accepted:
09
02
2023
pubmed:
16
2
2023
medline:
22
2
2023
entrez:
15
2
2023
Statut:
ppublish
Résumé
The acquisition of the cancer stem cell (CSC) properties is often mediated by the surrounding microenvironment, and tumor hypoxia is considered an important factor for CSC phenotype development. High levels of NRF2 (Nuclear Factor Erythroid 2-Like 2; NFE2L2), a transcription factor that maintains cellular redox balance, have been associated with facilitated tumor growth and therapy resistance. In this study, we investigated the role of NRF2 in hypoxia-induced CSC phenotypes in colorectal cancer cells. Chronic hypoxia for 72 h resulted in CSC phenotypes, including elevation of krupple-like factor 4 (KLF4) and octamer-binding transcription factor 4 (OCT4), and an increase in cancer migration and spheroid growth with concomitant hypoxia-inducible factor 2α (HIF-2α) accumulation. All these chronic hypoxia-induced CSC properties were attenuated following HIF-2α-specific silencing. In this chronic hypoxia model, NRF2 inhibition by shRNA-based silencing or brusatol treatment blocked HIF-2α accumulation, which consequently resulted in decreased CSC marker expression and inhibition of CSC properties such as spheroid growth. In contrast, NRF2 overactivation by genetic or chemical approach enhanced the chronic hypoxia-induced HIF-2α accumulation and cancer migration. As a molecular mechanism of the NRF2-inhibition-mediated HIF-2α dysregulation, we demonstrated that miR-181a-2-3p, whose expression is elevated in NRF2-silenced cells, targeted the HIF-2α 3'UTR and subsequently suppressed the chronic hypoxia-induced HIF-2α and CSC phenotypes. The miR-181a-2-3p inhibitor treatment in NRF2-silenced cells could restore the levels of HIF-2α and CSC markers, and increased cancer migration and sphere formation under chronic hypoxia. In line with this, the miR-181a-2-3p inhibitor transfection could increase tumorigenicity of NRF2-silenced colorectal cancer cells. Collectively, our study suggests the involvement of NRF2/miR181a-2-3p signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments.
Identifiants
pubmed: 36791645
pii: S2213-2317(23)00033-2
doi: 10.1016/j.redox.2023.102632
pmc: PMC9950657
pii:
doi:
Substances chimiques
NF-E2-Related Factor 2
0
MicroRNAs
0
Basic Helix-Loop-Helix Transcription Factors
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
102632Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest M − K Kwak has received research grants from National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) and The Catholic University of Korea.
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