Chronic arsenic exposure enhances metastatic potential via NRF2-mediated upregulation of SOX9.

Toxicology and Applied Pharmacology
Cody J SchmidlinDonna D Zhang

Abstract

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 express...Continue Reading

Citations

Feb 7, 2021·Toxicology and Applied Pharmacology·Yuanyuan XuJingbo Pi
Mar 9, 2021·Molecular Carcinogenesis·Cody J SchmidlinDonna D Zhang
May 1, 2021·Antioxidants·Aleksandra BuhaLuciano Saso
May 22, 2021·Seminars in Cancer Biology·Cody J SchmidlinDonna D Zhang

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