Chronic arsenic exposure enhances metastatic potential via NRF2-mediated upregulation of SOX9.
Arsenic
Cancer
Metastasis
NRF2
NSCLC
SOX9
Journal
Toxicology and applied pharmacology
ISSN: 1096-0333
Titre abrégé: Toxicol Appl Pharmacol
Pays: United States
ID NLM: 0416575
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
06
05
2020
revised:
30
06
2020
accepted:
11
07
2020
pubmed:
20
7
2020
medline:
7
1
2021
entrez:
20
7
2020
Statut:
ppublish
Résumé
Chronic low dose arsenic exposure continues to be a worldwide health concern because of its prevalence and link to increased cancer risk, including non-small cell lung cancer (NSCLC). Mortality of NSCLC patients increases with the development of a metastatic lesion compared to when the tumor is localized; however, the exact mechanism for what causes NSCLC cells to metastasize in the context of environmental toxicant exposure has yet to be fully elucidated. One proposed contributor to metastasis in NSCLC is nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor with known oncogenic properties that has proved to be critical for arsenic carcinogenesis. Here, we demonstrate that chronic arsenic exposure enhances the invasive and migratory capacity of immortalized lung epithelial cells via NRF2-dependent upregulation of SRY-box 9 (SOX9), another transcription factor linked with cell proliferation, epithelial-mesenchymal transition, and metastasis. We identified a functional antioxidant response element (ARE) in the promoter region of SOX9, suggesting that it is an NRF2 target gene, with mutation of the ARE preventing NRF2 binding. Pharmacological induction or inhibition of NRF2 increased or decreased SOX9 expression, respectively. Furthermore, we demonstrate that hyperactivation of NRF2 via knockout of Kelch-like ECH-associated protein 1 (KEAP1), its negative regulator, contributes to proliferation; while, inhibition of NRF2 or direct knockdown of SOX9 slowed the ability of NSCLC cells to proliferate, migrate, and invade. Overall, this study suggests that NRF2-mediated SOX9 upregulation can contribute to the metastatic potential of both environmentally and genetically driven lung tumors.
Identifiants
pubmed: 32682831
pii: S0041-008X(20)30264-7
doi: 10.1016/j.taap.2020.115138
pmc: PMC7594696
mid: NIHMS1615222
pii:
doi:
Substances chimiques
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
SOX9 Transcription Factor
0
SOX9 protein, human
0
Arsenic
N712M78A8G
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
115138Subventions
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES004940
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES031575
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES007091
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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