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Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells.

ABSTRACT: Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2B lung epithelial cells. The inhibition also occurs in A549 lung bronchial carcinoma cells. Cr(VI) suppresses Gene 33 expression mainly through post-transcriptional mechanisms, although the mRNA level of gene 33 also tends to be lower upon Cr(VI) treatments. Cr(VI)-induced DNA damage appears primarily in the S phases of the cell cycle despite the high basal DNA damage signals at the G2M phase. Knockdown of Gene 33 with siRNA significantly elevates Cr(VI)-induced DNA damage in both BEAS-2B and A549 cells. Depletion of Gene 33 also promotes Cr(VI)-induced micronucleus (MN) formation and cell transformation in BEAS-2B cells. Our results reveal a novel function of Gene 33 in Cr(VI)-induced DNA damage and lung epithelial cell transformation. We propose that in addition to its role in the canonical EGFR signaling pathway and other signaling pathways, Gene 33 may also inhibit Cr(VI)-induced lung carcinogenesis by reducing DNA damage triggered by Cr(VI).

SUBMITTER: Park S

PROVIDER: S-EPMC4891014 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells.

Park Soyoung S Li Cen C Zhao Hong H Darzynkiewicz Zbigniew Z Xu Dazhong D

Oncotarget 20160201 8

Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2 ...[more]

PMID: 26760771

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Project description:ObjectiveThe International Agency for Research on Cancer classifies hexavalent chromium (Cr(VI)) as a human carcinogen. As reported, cancer mortality was higher in Cr(VI)-contaminated areas. Scientists have recommended studying its health impact on people living in contaminated areas. This study aims to evaluate the health risk for people living in Cr(VI)-contaminated areas.DesignWe conducted a cross-sectional study in rural areas of north-eastern China. Malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) were used as oxidative stress parameters, and 8-hydroxy-2 deoxyguanosine (8-OHdG) as a DNA damage biomarker. We collected information on demographics, lifestyles and length of residence from all participants using a questionnaire. Biological specimens and environmental media samples were collected on the same day as the survey was done. We used t-test, χ2 test, Wilcoxon rank-sum test and multivariate linear regression analysis.ParticipantsThe study included 319 participants exposed to Cr(VI) and 307 unexposed participants, with 447 women and 179 men. These participants met the following criteria: (1) living in the areas for more than 10 years; (2) age older than 18 years; and (3) without occupational chromium exposure.ResultsOur study revealed that serum concentration of MDA (p<0.001), serum activities of CAT (p<0.001) and GSH-Px (p<0.001), as well as urine concentration of 8-OHdG (p=0.008) in the exposed group were significantly higher than those in the unexposed group. However, serum SOD activity was significantly lower in the exposed group, compared with that in the unexposed group (p<0.001). Cr(VI) exposure and smoking have an interaction effect on GSH-Px activity (p<0.05). Cr(VI) exposure and alcohol drinking also have an interaction effect on GSH-Px activity (p<0.05). Longer residence in the exposed areas increased the oxidative levels (p<0.05).ConclusionsThe findings of this study showed elevated oxidative stress and DNA damage in people exposed to Cr(VI).

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Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells.

Publications

Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells.

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