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. 2019 Jun 17;32(6):1299-1309.
doi: 10.1021/acs.chemrestox.9b00089. Epub 2019 Jun 4.

Arsenic-Induced Neoplastic Transformation Involves Epithelial-Mesenchymal Transition and Activation of the β-Catenin/c-Myc Pathway in Human Kidney Epithelial Cells

Yu-Wei Chang  1 , Kamaleshwar P Singh  1
Affiliations

Arsenic-Induced Neoplastic Transformation Involves Epithelial-Mesenchymal Transition and Activation of the β-Catenin/c-Myc Pathway in Human Kidney Epithelial Cells

Yu-Wei Chang et al. Chem Res Toxicol. .

Abstract

Arsenic contamination is a serious environmental and public health issue worldwide including the United States. Accumulating evidence suggests that kidney is one of the target organs for arsenic-induced carcinogenesis. However, the mechanism of arsenic-induced renal carcinogenesis is not well understood. Therefore, the objective of this study was to evaluate the carcinogenicity of chronic exposure to an environmentally relevant concentration of arsenic on kidney epithelial cells and identify the molecular mechanism underlying this process. HK-2 kidney epithelial cells were treated with arsenic for acute, long-term, and chronic durations, and cellular responses to arsenic exposure at these time points were evaluated by the changes in growth, morphology, and expression of genes. The results revealed a significant growth increase after long-term and chronic exposure to arsenic in HK-2 cells. The morphological changes of EMT and stem cell sphere formation were also observed in long-term arsenic exposed cells. The anchorage-independent growth assay for colony formation and cell maintenance in cancer stem cell medium further confirmed neoplastic transformation and the induced cancer stem cell properties of arsenic-exposed cells. Additionally, the expression of marker genes confirmed the increased growth, EMT, and stemness during arsenic-induced carcinogenesis. Moreover, the increase expression of β-catenin and c-Myc further suggested the role of these signaling molecules during carcinogenesis in HK-2 cells. In summary, results of this study suggest that chronic exposure to arsenic even at a relatively lower concentration can induce neoplastic transformation through acquisitions of EMT, stemness, and MET phenotypes, which might be related to the β-catenin/c-Myc signaling pathway.

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