Arsenic Induces Overexpression of Growth Factors in Human Keratinocytes

GERMOLEC, D; YOSHIDA, T; GAIDO, K; WILMER, J; SIMEONOVA, P; KAYAMA, F; BURLESON, F; DONG, W; LANGE, R; LUSTER, M

doi:10.1006/taap.1996.0288

Cited by 44 publications

(62 citation statements)

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“…Clinical studies in arsenic-induced Bowen's disease (As-BD) indicate that the increased 8-OHdG levels are positively correlated to the lesional arsenic concentration [26], suggesting the involvement of oxidative stress in arsenical skin carcinogenesis. In vitro studies indicated that ROS induced by low concentrations of arsenic (<5 lM) can increase the transcription of the activator protein-1 (AP-1) and the nuclear factor kappa B (NF-jB) [27][28][29][30], which results in subsequent stimulation of cell proliferation [31,32].…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

“…In which, the abnormalities in growth factor expression, cell cycle regulation, and apoptotic signaling are most closely associated with arsenic carcinogenesis. It is reported that long-term low dose arsenic exposure can enhance cellular sensitivity and response to epithelial growth factor (EGF) [31,58] which can further inhibit cell cycle inhibitory protein p27 expression and cause cell hyperproliferation via c-myc and E2F-1 regulatory pathway [59]. Arsenic can also enhance keratinocytes to express TGF-a, GM-CSF, IL-6 and IL-8 [31,58,60].…”

Section: Altered Transcription Factorsmentioning

confidence: 99%

“…It is reported that long-term low dose arsenic exposure can enhance cellular sensitivity and response to epithelial growth factor (EGF) [31,58] which can further inhibit cell cycle inhibitory protein p27 expression and cause cell hyperproliferation via c-myc and E2F-1 regulatory pathway [59]. Arsenic can also enhance keratinocytes to express TGF-a, GM-CSF, IL-6 and IL-8 [31,58,60]. These arsenic-induced growth factors and cytokines expression are reported to associate with arsenic-induced cutaneous tumorigenesis via AP-1 and NF-jB regulation [61].…”

Section: Altered Transcription Factorsmentioning

confidence: 99%

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Arsenic Carcinogenesis in the Skin

2006

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SummaryChronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this

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Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Section: Altered Transcription Factorsmentioning

confidence: 99%

Section: Altered Transcription Factorsmentioning

confidence: 99%

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Arsenic Carcinogenesis in the Skin

2006

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“…Chronic exposure to As leads to skin disorders such as hyperkeratosis and, in many cases, carcinogenesis (12,13). Both As and Cr, a well-known skin sensitizer, have substantial effects on epidermal keratinocytes in vitro and in vivo; these metals have been shown to alter expression of numerous growth regulatory factors, to stimulate cell proliferation at low concentrations, and to inhibit the normal process of differentiation (11,(14)(15)(16)(17)(18)(19). They have not, however, been shown to be directly transforming in this cell type.…”

mentioning

confidence: 99%

Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes: application of cDNA microarray technology.

Bae

Hanneman

Yang

et al. 2002

Environ Health Perspect

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“…Cambronero and Veatch (1996) have also indicated the involvement of c-myc in the GM-CSF signaling pathway. Germolec et al (1996) have reported increased cell proliferation along with increased expression of c-myc gene and increased transcription of GM-CSF as a result of arsenic treatment, again depicting an association between cell proliferation, c-myc and GM-CSF. In view of the above-mentioned reports, it would be plausible to assume a close relationship among CSFs (especially GM-CSF), DHFR, and white blood cells proliferation.…”

Section: Discussionmentioning

confidence: 92%

Increased levels of multiple forms of dihydrofolate reductase in peripheral blood leucocytes of cancer patients receiving haematopoietic colony-stimulating factors: Interim analysis

Iqbal

Burney²,

Sultana³

et al. 2000

Exp Mol Med

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The precise mechanism whereby granulocytes proliferate when haematopoietic colony stimulating factors (CSFs) are used in neutropenic cancer patients is poorly understood. The purpose of this study was to investigate whether these cytokines bring about leucocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase (DHFR). Blood samples were collected from 36 cancer patients (25 males and 11 females) with chemotherapy-induced neutropenia. One sample of blood from each patient was obtained before therapy either with CSF, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) or with placebo, and another one at the time of resolution of neutropenia. Peripheral blood leucocytes in these blood samples were counted, separated and lysed. From lysates, cytoplasmic samples were prepared and analyzed for active DHFR by a methotrexate-binding assay and for total immunoreactive DHFR by an enzyme linked immunosorbent assay. The increase in total leucocyte count (TLC) was most prominent (P < 0.005) in the CSF group and less so (P < 0.05) in the placebo group. The mean ± SD concentration values of active DHFR before and after stimulation with GM-CSF found were to be 0.34 ± 0.4 ng/mg protein and 0.99 ± 0.82 ng/mg protein, respectively, and in the group treated with G-CSF, 0.24 ± 0.32 ng/mg protein and 1.18 ± 2.4 ng/mg protein, respectively. This increase in active DHFR after stimulation with CSF was statistically significant (P < 0.05). Similarly, concentration values of immunoreactive but nonfunctional form of DHFR (IRE) were 110 ± 97 ng/mg protein and 605 ± 475 ng/mg protein before and after stimulation with GM-CSF, and 115 ± 165 ng/mg protein and 1054 ± 1095 ng/ mg protein before and after stimulation with G-CSF. This increase in concentration of IRE after stimulation with GM-CSF or G-CSF was statistically significant (P < 0.005). In the control group, there was an increase in the concentration of both active DHFR and IRE after treatment with placebo. However, this was not statistically significant. Resolution of neutropenia was quicker in the groups treated with CSF compared to the control group. Results of this study indicate that colony stimulating factors (G-CSF and GM-CSF) induce white cell proliferation by increasing the levels of multiple forms of DHFR.

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Arsenic Induces Overexpression of Growth Factors in Human Keratinocytes

Cited by 44 publications

References 0 publications

Arsenic Carcinogenesis in the Skin

Arsenic Carcinogenesis in the Skin

Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes: application of cDNA microarray technology.

Increased levels of multiple forms of dihydrofolate reductase in peripheral blood leucocytes of cancer patients receiving haematopoietic colony-stimulating factors: Interim analysis

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