Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes

Nail, Alexandra N.; McCaffrey, Lakynkalina M.; Banerjee, Minakshi; Cardoso, Ana Paula Ferragut; States, J. Christopher

doi:10.1016/j.taap.2022.116042

Cited by 14 publications

(2 citation statements)

References 80 publications

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“…Recent reports have indicated that chronic low-to-moderate arsenic exposure elevates the risk of urothelial tract cancers, for instance, bladder cancer and upper urothelial tract cancer [ 33 , 34 ]. In vitro studies also proved that chronic exposure to low concentrations of arsenic can induce malignant transformation of various cells, including HaCaT cells [ 35 , 36 , 37 ]. However, there is not yet agreement on the mechanisms underlying the arsenic-induced malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

MiR-96-5p Suppresses Progression of Arsenite-Induced Human Keratinocyte Proliferation and Malignant Transformation by Targeting Denticleless E3 Ubiquitin Protein Ligase Homolog

Li,

Zhao,

Yao

et al. 2023

Toxics

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Long-term exposure to arsenic has been linked to a variety of cancers, among which skin cancer is the most prevalent form. However, the mechanism underlying arsenic carcinogenesis is unclear, and there is still limited information on the role of miRNAs in arsenic-induced skin cancer. This study aims to explore the role of miR-96-5p in the arsenite-induced proliferation and malignant transformation of human HaCaT keratinocytes. The GEO database (accession numbers GSE97303, GSE97305, and GSE97306) was used to extract mRNA and miRNA expression profiles of HaCaT cells treated with or without 0.1 μmol/L sodium arsenite for 3 and 7 weeks. In this paper, according to the CCK8 assay result, HaCaT cells exposed to 0.1 μmol/L sodium arsenite for 48 h were finalized. CCK8, MTT, EdU incorporation, and colony formation assays were used to determine the viability and proliferation of HaCaT cells and transformed HaCaT (T-HaCaT) cells. The subcellular localization and relative expression levels of DTL, as well as miR-96-5p in HaCaT cells induced by arsenite, were determined via immunofluorescence, RT-qPCR, and Western blot. Dual-luciferase reporter assay was performed to identify miR-96-5p bound directly to DTL. Transfection of miR-96-5p mimics or DTL siRNA was conducted to verify the arsenite-induced viability of HaCaT cells and T-HaCaT cells. T-HaCaT cells and nude mice were used to construct arsenite-induced malignant transformation and an in vivo xenograft model to demonstrate the over-expressed effect of miR-96-5p. The results showed that DTL was the target gene of miR-96-5p. Meanwhile, we also found that 0.1 μmol/L sodium arsenite upregulated DTL by decreasing the miR-96-5p level, leading to the proliferation and malignant transformation of HaCaT cells. MiR-96-5p agomir treatment slowed the growth of transplanted HaCaT cells transformed by arsenite in a manner associated with DTL downregulation in the nude mice xenograft model. Taken together, we confirmed that miR-96-5p, as a potent regulator of DTL, suppressed arsenite-induced HaCaT cell proliferation and malignant transformation, which might provide a novel therapeutic target for the treatment of arsenic-induced skin cancer.

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Section: Discussionmentioning

confidence: 99%

MiR-96-5p Suppresses Progression of Arsenite-Induced Human Keratinocyte Proliferation and Malignant Transformation by Targeting Denticleless E3 Ubiquitin Protein Ligase Homolog

Li,

Zhao,

Yao

et al. 2023

Toxics

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“…We also showed that arsenic induced supernumerary motor neuron development via activation of the Sonic hedgehog (Shh) pathway (Kanungo et al, 2023). Inorganic arsenic modulates several signaling pathways (Chen & Costa, 2018; Laine & Fry, 2018; Nail et al, 2022; Phillips et al, 2020). Determining gene expression changes related to various signaling pathways can improve understanding of the mechanism of toxicity of drugs and chemicals.…”

Section: Introductionmentioning

confidence: 99%

Gene expression analyses reveal potential mechanism of inorganic arsenic‐induced apoptosis in zebrafish

Silva,

Kudlyk,

Tryndyak

et al. 2023

J of Applied Toxicology

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Our previous study showed that sodium arsenite (200 mg/L) affected the nervous system and induced motor neuron development via the Sonic hedgehog pathway in zebrafish larvae. To gain more insight into the effects of arsenite on other signaling pathways, including apoptosis, we have performed quantitative polymerase chain reaction array‐based gene expression analyses. The 96‐well array plates contained primers for 84 genes representing 10 signaling pathways that regulate several biological functions, including apoptosis. We exposed eggs at 5 h postfertilization until the 72 h postfertilization larval stage to 200 mg/L sodium arsenite. In the Janus kinase/signal transducers and activators of transcription, nuclear factor κ‐light‐chain‐enhancer of activated B cells, and Wingless/Int‐1 signaling pathways, the expression of only one gene in each pathway was significantly altered. The expression of multiple genes was altered in the p53 and oxidative stress pathways. Sodium arsenite induced excessive apoptosis in the larvae. This compelled us to analyze specific genes in the p53 pathway, including cdkn1a, gadd45aa, and gadd45ba. Our data suggest that the p53 pathway is likely responsible for sodium arsenite‐induced apoptosis. In addition, sodium arsenite significantly reduced global DNA methylation in the zebrafish larvae, which may indicate that epigenetic factors could be dysregulated after arsenic exposure. Together, these data elucidate potential mechanisms of arsenic toxicity that could improve understanding of arsenic's effects on human health.

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Heavy-metal associated breast cancer and colorectal cancer hot spots and their demographic and socioeconomic characteristics

Tomlinson,

Pugh,

Nail

et al. 2024

Cancer Causes Control

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Purpose Cancer registries offer an avenue to identify cancer clusters across large populations and efficiently examine potential environmental harms affecting cancer. The role of known metal carcinogens (i.e., cadmium, arsenic, nickel, chromium(VI)) in breast and colorectal carcinogenesis is largely unknown. Historically marginalized communities are disproportionately exposed to metals, which could explain cancer disparities. We examined area-based metal exposures and odds of residing in breast and colorectal cancer hotspots utilizing state tumor registry data and described the characteristics of those living in heavy metal-associated cancer hotspots. Methods Breast and colorectal cancer hotspots were mapped across Kentucky, and area-based ambient metal exposure to cadmium, arsenic, nickel, and chromium(VI) were extracted from the 2014 National Air Toxics Assessment for Kentucky census tracts. Among colorectal cancer (n = 56,598) and female breast cancer (n = 77,637) diagnoses in Kentucky, we used logistic regression models to estimate Odds Ratios (ORs) and 95% Confidence Intervals to examine the association between ambient metal concentrations and odds of residing in cancer hotspots, independent of individual-level and neighborhood risk factors. Results Higher ambient metal exposures were associated with higher odds of residing in breast and colorectal cancer hotspots. Populations in breast and colorectal cancer hotspots were disproportionately Black and had markers of lower socioeconomic status. Furthermore, adjusting for age, race, tobacco and neighborhood factors did not significantly change cancer hotspot ORs for ambient metal exposures analyzed. Conclusion Ambient metal exposures contribute to higher cancer rates in certain geographic areas that are largely composed of marginalized populations. Individual-level assessments of metal exposures and cancer disparities are needed.

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Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes

Cited by 14 publications

References 80 publications

MiR-96-5p Suppresses Progression of Arsenite-Induced Human Keratinocyte Proliferation and Malignant Transformation by Targeting Denticleless E3 Ubiquitin Protein Ligase Homolog

MiR-96-5p Suppresses Progression of Arsenite-Induced Human Keratinocyte Proliferation and Malignant Transformation by Targeting Denticleless E3 Ubiquitin Protein Ligase Homolog

Gene expression analyses reveal potential mechanism of inorganic arsenic‐induced apoptosis in zebrafish

Heavy-metal associated breast cancer and colorectal cancer hot spots and their demographic and socioeconomic characteristics

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