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Journal of Applied Toxicology

Journal of Applied Toxicology

IF: 2.8
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Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1

Published:1 March 2023 DOI: 10.1002/jat.4457 PMID: 36861143
Jiafeng Chen, Cece Lei, Daibang Nie, Huan Ge, Jian Li, Changbin Lei, Wang Wang

Abstract

Inorganic arsenic (iAs) has been a human health concern and is associated with intestinal malignancies. However, the molecular mechanisms of the iAs-induced oncogenic process in intestine epithelial cells remain elusive, partly because of the known hormesis effect of arsenic. Here, we established that six-month exposure to iAs at a concentration similar to those found in contaminated drinking water could promote malignant characteristics, including enhanced proliferation and migration, resistance to apoptosis, and mesenchymal-like transition in Caco-2 cells. Transcriptome analysis and mechanism study revealed that key genes and pathways involved in cell adhesion, inflammation and oncogenic regulation were altered during chronic iAs exposure. Specifically, we uncovered that down-regulation of HTRA1 was essential for the iAs-induced acquisition of the cancer hallmarks. Further, we evidenced that the loss of HTRA1 during iAs-exposure could be restored by HDAC6 inhibition. Caco-2 cells with chronic exposure to iAs exhibited enhanced sensitivity to WT-161, a specific inhibitor of HDAC6, when used alone than in combination with a chemotherapeutic agent. These findings provide valuable information for understanding the mechanisms of arsenic-induced carcinogenesis and facilitating the health management of populations in arsenic-polluted areas.

Substances (16)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Gefitinib 184475-35-2 C22H24ClFN4O3 823 suppliers $5.00-$1191.00
Gefitinib 184475-35-2 C22H24ClFN4O3 823 suppliers $5.00-$1191.00
Gefitinib 184475-35-2 C22H24ClFN4O3 823 suppliers $5.00-$1191.00
Gefitinib 184475-35-2 C22H24ClFN4O3 823 suppliers $5.00-$1191.00
Tirbanibulin 897016-82-9 C26H29N3O3 135 suppliers $19.00-$1750.00
Tirbanibulin 897016-82-9 C26H29N3O3 135 suppliers $19.00-$1750.00
Tirbanibulin 897016-82-9 C26H29N3O3 135 suppliers $19.00-$1750.00
Tirbanibulin 897016-82-9 C26H29N3O3 135 suppliers $19.00-$1750.00
BMS 582949 623152-17-0 C22H26N6O2 81 suppliers $29.00-$2689.00
BMS 582949 623152-17-0 C22H26N6O2 81 suppliers $29.00-$2689.00

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