Chronic and acute arsenic exposure enhance EGFR expression via distinct molecular mechanisms

Kim, Christine; States, J. Christopher; Ceresa, Brian P.

doi:10.1016/j.tiv.2020.104925

Cited by 10 publications

(4 citation statements)

References 59 publications

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“…Thus, in human BEAS-2B cells, increased EGFR protein levels were observed after acute (24 h) and chronic (24 week) arsenite exposure, albeit involving different mechanisms. While the elevated expression of TGFα was observed after long-term treatment, accompanied by increased EGFR phosphorylation and elevated cell surface EGFR levels, no concomitant increase in TGFα expression was evident after 24 h, suggesting time-dependent differences in the molecular mechanisms of EGFR activation [33].…”

Section: Discussionmentioning

confidence: 90%

Effect of Long-Term Low-Dose Arsenic Exposure on DNA Methylation and Gene Expression in Human Liver Cells

Stößer,

Lumpp,

Fischer

et al. 2023

IJMS

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Millions of people around the world are exposed to elevated levels of arsenic through food or drinking water. Epidemiological studies have linked chronic arsenic exposure to an increased risk of several cancers, cardiovascular disease, central nervous system neuropathies, and genotoxic as well as immunotoxic effects. In addition to the induction of oxidative stress and inhibition of DNA repair processes, epigenetic effects, including altered DNA methylation patterns resulting in aberrant gene expression, may contribute to carcinogenicity. However, the underlying mechanisms by which chronic micromolar concentrations of arsenite affect the methylation status of DNA are not fully understood. In this study, human HepG2 hepatocarcinoma cells were treated with 0.5–10 μM sodium arsenite for 24 h, 10, or 20 days. During these periods, the effects on global DNA methylation, cell cycle phase distribution, and gene expression were investigated. While no impact on DNA methylation was seen after short-term exposure, global hypomethylation was observed at both long-term exposure periods, with concomitant induction of the DNA methyltransferase genes DNMT1 and DNMT3B, while DNMT3A was slightly down-regulated. Pronounced time- and concentration-dependent effects were also seen in the case of genes involved in DNA damage response and repair, inflammation, oxidative stress response, and metal homeostasis. These results suggest that chronic low-dose arsenite exposure can lead to global hypomethylation. As an underlying mechanism, the consistent down-regulation of DNA methyltransferase genes could be excluded; alternatively, interactions at the protein level could play an important role.

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Section: Discussionmentioning

confidence: 90%

Effect of Long-Term Low-Dose Arsenic Exposure on DNA Methylation and Gene Expression in Human Liver Cells

Stößer,

Lumpp,

Fischer

et al. 2023

IJMS

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“…HIF-1α activation is important for tumorigenicity and angiogenesis in nude mice [64][65][66]; it is overexpressed in human cancers and is associated with angiogenesis induced by tumors and hypoxia [67,68]. It has been reported that EGFR activation is induced by arsenic exposure [20][21][22], and long-term exposure to arsenic at low doses results in increased EGFR expression due to inducing TGFα [11]. We also found that chronic arsenic exposure activates the EGFR/p-ERK/HIF-1α pathway [69].…”

Section: Discussionmentioning

confidence: 99%

“…Both acute and chronic arsenic toxicities generate harmful effects in multiple organs and tissues, such as hyperkeratosis, change in skin pigmentation, cardiovascular diseases, and developmental and cognitive impairments. The epidermal growth factor receptor (EGFR), a tyrosine kinase receptor of the ErbB/HER oncogene, is among the cancer-related targets [11]. EGFR mutation or overexpression has an essential role in tumorigenesis in different types of cancers, including non-small-cell lung cancer (NSCLC) [12], breast cancer [13], colorectal cancer [14], and gastric carcinoma [15].…”

Section: Introductionmentioning

confidence: 99%

MiR-218-5p/EGFR Signaling in Arsenic-Induced Carcinogenesis

Islam

Zhao

Zhang

et al. 2023

Cancers

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Background: Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear. Methods: RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR signaling. Results: EGFR and miR-218-5p were dramatically upregulated and downregulated in arsenic-induced transformed (As-T) cells, respectively. MiR-218-5p acted as a tumor suppressor to inhibit cell proliferation, migration, colony formation, tube formation, tumor growth, and angiogenesis. Furthermore, miR-218-5p directly targeted EGFR by binding to its 3′-untranslated region (UTR). Finally, miR-218-5p exerted its antitumor effect by inhibiting its direct target, EGFR. Conclusion: Our study highlights the vital role of the miR-218-5p/EGFR signaling pathway in arsenic-induced carcinogenesis and angiogenesis, which may be helpful for the treatment of lung cancer induced by chronic arsenic exposure in the future.

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“…In another study, cells treated with acute exposure of As exhibited a decrease in viability and changes in morphology. In contrast, during 24 weeks of As exposure, the cells had increased EGFR expression and activity and increased mRNA and protein levels of TGFα [ 54 ]. We found overexpressed EGFR in BCC both in high and low As exposure.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Arsenic Exposure and Transcriptomic Profile in Basal Cell Carcinoma

Kibriya

Jasmine

Muñoz

et al. 2022

Cancers

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Exposure to inorganic arsenic (As) is recognized as risk factor for basal cell carcinoma (BCC). We have followed-up 7000 adults for 6 years who were exposed to As and had manifest As skin toxicity. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%). In this study, we compared transcriptome-wide RNA sequencing data from the very first 26 BCC cases and healthy skin tissue from independent 16 individuals. Genes in “ cell carcinoma pathway”, “Hedgehog signaling pathway”, and “Notch signaling pathway” were overexpressed in BCC, confirming the findings from earlier studies in BCC in other populations known to be exposed to As. However, we found that the overexpression of these known pathways was less pronounced in patients with high As exposure (urinary As creatinine ratio (UACR) > 192 µg/gm creatinine) than patients with low UACR. We also found that high UACR was associated with impaired DNA replication pathway, cellular response to different DNA damage repair mechanisms, and immune response. Transcriptomic data were not strongly suggestive of great potential for immune checkpoint inhibitors; however, it suggested lower chance of platinum drug resistance in BCC patients with high UACR compared high platinum drug resistance potential in patients with lower UACR.

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Chronic and acute arsenic exposure enhance EGFR expression via distinct molecular mechanisms

Cited by 10 publications

References 59 publications

Effect of Long-Term Low-Dose Arsenic Exposure on DNA Methylation and Gene Expression in Human Liver Cells

Effect of Long-Term Low-Dose Arsenic Exposure on DNA Methylation and Gene Expression in Human Liver Cells

MiR-218-5p/EGFR Signaling in Arsenic-Induced Carcinogenesis

Interaction of Arsenic Exposure and Transcriptomic Profile in Basal Cell Carcinoma

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