Subchronic Exposure to Arsenic Through Drinking Water Alters Expression of Cancer-Related Genes in Rat Liver

Chen, Xing; Song, Li; Shraim, Amjad; Kobayashi, Yayoi; Hayakawa, Tõru; Kanno, Sanae; Yamamoto, Megumi; Hirano, Seishiro

doi:10.1080/01926230490261348

Cited by 45 publications

(10 citation statements)

References 54 publications

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“…Thus, the loss of this protective factor could help explain the induction of ODD seen in this study. Moreover, this MMA III -induced depletion of PTEN expression is consistent with that seen during malignant transformation and tumor formation by other arsenicals (Cui et al 2004; Tokar et al, 2010a; Sun et al 2012), suggesting a common mechanism in several models of arsenical-induced carcinogenesis. Previous studies have shown that arsenicals (iAs, MMA III ) can alter signaling via Akt phosphorylation but these exposures had no effect on PTEN levels (Paul et al 2007).…”

Section: Discussionsupporting

confidence: 80%

“…For instance, phosphatase and tensin homologue (PTEN) is a tumor suppressor gene that is commonly mutated or deleted in cancers, but plays vital roles in proper DNA repair and DNA damage response pathways (Ming and He, 2012). Chronic exposure to arsenic depletes the expression of PTEN during cancer formation in vivo and during malignant transformation in vitro (Cui et al 2004; Tokar et al, 2010a; Sun et al 2012). Thus, not only can exposure to arsenicals induce ROS-mediated ODD (Nesnow et al, 2002; Gomez et al, 2006; Kojima et al, 2009; Wnek et al, 2011), it can also inactivate various factors involved in DNA repair, thereby perturbing the repair process (Cui et al 2004; Tokar et al, 2010a; Wnek et al, 2011; Sun et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Methylarsonous acid causes oxidative DNA damage in cells independent of the ability to biomethylate inorganic arsenic

2013

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Inorganic arsenic (iAs) and its toxic methylated metabolite, methylarsonous acid (MMAIII), both have carcinogenic potential. Prior study shows iAs induced malignant transformation in both arsenic methylation-proficient (liver) and methylation-deficient (prostate) cells, but only methylation-proficient cells show oxidative DNA damage (ODD) during this transformation. To further define if arsenic methylation is necessary for transformation or ODD induction, here we chronically exposed these same liver or prostate cell lines to MMAIII (0.25–1.0 μM) and tested for acquired malignant phenotype. Various metrics of oncogenic transformation were periodically assessed along with ODD during chronic MMAIII exposure. Methylation-deficient and methylation-proficient cells both acquired a cancer phenotype with MMAIII exposure at about 20 weeks, based on increased matrix metalloproteinase secretion, colony formation and invasion. In contrast, prior work showed iAs-induced transformation took longer in biomethylation-deficient cells (~30 weeks) than in biomethylation-proficient cells (~18 weeks). In the present study, MMAIII caused similar peak ODD levels at similar concentrations and at similar exposure times (18–22 weeks) in both cell types. At the approximate peak of ODD production both cell types showed similar alterations in arsenic and oxidative stress adaptation factors (i.e. ABCC1, ABCC2, GST-π, SOD-1). Thus, MMAIII causes oncogenic transformation associated with ODD in methylation-deficient cells, indicating further methylation is not required to induce ODD. Together, these results show that, MMAIII and iAs cause an acquired malignant phenotype in methylation-deficient cells, yet iAs does not induce ODD. This indicates iAs likely has both genotoxic and non-genotoxic mechanisms dictated by the target cell’s ability to methylate arsenic.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Methylarsonous acid causes oxidative DNA damage in cells independent of the ability to biomethylate inorganic arsenic

2013

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“…Cyclin D1 overexpression is important for HCC formation and is considered a hepatic oncogene (Deane et al 2001). Overexpression of cyclin D1 has been reported in arsenic-transformed cells (Chen et al 2001b), during arsenic-induced skin co-carcinogenicity in mice (Rossman et al 2001), in dimethylarsinic acid–induced bladder proliferative lesions in rats (Wei et al 2002), in chronic arsenate-exposed rats (Cui et al 2004), and in the livers of mice bearing HCC induced by in utero exposure to arsenic (Liu et al 2004). Cyclin D1 overexpression, together with other positive cell cycle regulators such as cyclin E, cdk4, cdkn2a, cdkn2b, and PCNA was evident in arsenic-exposed tissues in the present study.…”

Section: Discussionmentioning

confidence: 99%

Global Gene Expression Associated with Hepatocarcinogenesis in Adult Male Mice Induced by in Utero Arsenic Exposure

Liu

Xie²,

Ducharme³

et al. 2006

Environ Health Perspect

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Our previous work has shown that exposure to inorganic arsenic in utero produces hepatocellular carcinoma (HCC) in adult male mice. To explore further the molecular mechanisms of transplacental arsenic hepatocarcinogenesis, we conducted a second arsenic transplacental carcinogenesis study and used a genomewide microarray to profile arsenic-induced aberrant gene expression more extensively. Briefly, pregnant C3H mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from days 8 to 18 of gestation. The incidence of HCC in adult male offspring was increased 4-fold and tumor multiplicity 3-fold after transplacental arsenic exposure. Samples of normal liver and liver tumors were taken at autopsy for genomic analysis. Arsenic exposure in utero resulted in significant alterations (p < 0.001) in the expression of 2,010 genes in arsenic-exposed liver samples and in the expression of 2,540 genes in arsenic-induced HCC. Ingenuity Pathway Analysis revealed that significant alterations in gene expression occurred in a number of biological networks, and Myc plays a critical role in one of the primary networks. Real-time reverse transcriptase–polymerase chain reaction and Western blot analysis of selected genes/proteins showed > 90% concordance. Arsenic-altered gene expression included activation of oncogenes and HCC biomarkers, and increased expression of cell proliferation–related genes, stress proteins, and insulin-like growth factors and genes involved in cell–cell communications. Liver feminization was evidenced by increased expression of estrogen-linked genes and altered expression of genes that encode gender-related metabolic enzymes. These novel findings are in agreement with the biology and histology of arsenic-induced HCC, thereby indicating that multiple genetic events are associated with transplacental arsenic hepatocarcinogenesis.

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“…For an example, Park and his colleagues report that p27 Kip1 expression is not altered in arsenic trioxide-induced cell cycle arrest and apoptosis in myeloma cells [8]. While another study demonstrates that p27 Kip1 mRNA level is increased after a 4-month arsenic exposure [9]. Recently, arsenic trioxide is also reported to induce p27 Kip1 expression in breast cancer cell line and hepatocellular carcinoma (HCC) cells [10,11].…”

Section: Introductionmentioning

confidence: 99%

IKK-β/NF-κB p65 mediates p27Kip1 protein degradation in arsenite response

Guo

Liu

Jian

et al. 2014

Biochemical and Biophysical Research Communications

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p27kip1 is a potent inhibitor of the cyclin-dependent kinases that drive G1 to S phase transition. Since deregulation of p27kip1 is found in many malignancies and is associated with the poor prognosis, elucidation of the molecular bases for regulation of p27kip1 expression is of great significance, not only in providing insight into the understanding of biological p27kip1, but also in the development of new cancer therapeutic tactics. We here explored the inhibitory regulation of IKKβ on p27 expression following arsenite exposure. We found that although the basal level of p27 expression in the IKKβ−/− cells is much lower than that in the IKKβ+/+ cells, the deletion of IKKβ in the MEFs led to a marked increase in p27kip1 protein induction due to arsenite exposure in comparison to that in the IKKβ+/+ cells. The IKKβ regulatory effect on p27 expression was also verified in the IKKβ−/− and IKKβ−/− cells with IKKβ reconstitutional expression, IKKβ−/−(IKKβ). Further studies indicated that IKKβ-mediated p27 downregulation occurred at protein degradation level via p65-dependent and p50-independent manner. Moreover, the results obtained from the comparison of arsenite-induced GSK3β activation among transfectants of WT, IKKβ−/− and IKKβ−/−(IKKβ), and the utilization of GSKβ shRNA, demonstrated that IKKβ regulation of p27 protein degradation was mediated by GSK3β following arsenite exposure.

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Subchronic Exposure to Arsenic Through Drinking Water Alters Expression of Cancer-Related Genes in Rat Liver

Cited by 45 publications

References 54 publications

Methylarsonous acid causes oxidative DNA damage in cells independent of the ability to biomethylate inorganic arsenic

Methylarsonous acid causes oxidative DNA damage in cells independent of the ability to biomethylate inorganic arsenic

Global Gene Expression Associated with Hepatocarcinogenesis in Adult Male Mice Induced by in Utero Arsenic Exposure

IKK-β/NF-κB p65 mediates p27Kip1 protein degradation in arsenite response

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