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Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay.

ABSTRACT: Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes. One key cellular process is epithelial-mesenchymal transition (EMT) where epithelial sheets develop into three-dimensional structures. An embryonic prototype of EMT is found in the atrioventricular (AV) canal of the developing heart, where endothelia differentiate to form heart valves. Effects of arsenic on this cellular process were examined by collagen gel invasion assay (EMT assay) using explanted AV canals from chicken embryo hearts. AV canals treated with 12.5-500 ppb arsenic showed a loss of mesenchyme at 12.5 ppb, and mesenchyme formation was completely inhibited at 500 ppb. Altered gene expression in arsenic-treated explants was investigated by microarray analysis. Genes whose expression was altered consistently at exposure levels of 10, 25, and 100 ppb were identified, and results showed that 25 ppb in vitro was particularly effective. Three hundred and eighty two genes were significantly altered at this exposure level. Cytoscape analysis of the microarray data using the chicken interactome identified four clusters of altered genes based on published relationships and pathways. This analysis identified cytoskeleton and cell adhesion-related genes whose disruption is consistent with an altered ability to undergo EMT. These studies show that EMT is sensitive to arsenic and that an interactome-based approach can be useful in identifying targets.

SUBMITTER: Lencinas A

PROVIDER: S-EPMC2886855 | biostudies-other | 2010 Jul

REPOSITORIES: biostudies-other

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Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay.

Lencinas Alejandro A Broka Derrick M DM Konieczka Jay H JH Klewer Scott E SE Antin Parker B PB Camenisch Todd D TD Runyan Raymond B RB

Toxicological sciences : an official journal of the Society of Toxicology 20100322 1

Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes. One key cellular process is epithelial-mesenchymal transition (EMT) where epithelial sheets develop into three-dimensional structures. An ...[more]

PMID: 20308225

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Project description:BackgroundGliomas account for the majority of fatal primary brain tumors, and there is much room for research in the underlying pathogenesis, the multistep progression of glioma, and how to improve survival. In our study, we aimed to identify potential biomarkers or therapeutic targets of glioma and study the mechanism underlying the tumor progression.MethodsWe downloaded the microarray datasets (GSE43378 and GSE7696) from the Gene Expression Omnibus (GEO) database. Then, we used weighted gene co-expression network analysis (WGCNA) to screen potential biomarkers or therapeutic targets related to the tumor progression. ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumors using Expression data) algorithm and TIMER (Tumor Immune Estimation Resource) database were used to analyze the correlation between the selected genes and the tumor microenvironment. Real-time reverse transcription polymerase chain reaction was used to measure the selected gene. Transwell and wound healing assays were used to measure the cell migration and invasion capacity. Western blotting was used to test the expression of epithelial-mesenchymal transition (EMT) related markers.ResultsWe identified specific module genes that were positively correlated with the WHO grade but negatively correlated with OS of glioma. Importantly, we identified that 6 collagen genes (COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, and COL5A2) could regulate the immunosuppressive microenvironment of glioma. Moreover, we found that these collagen genes were significantly involved in the EMT process of glioma. Finally, taking COL3A1 as a further research object, the results showed that knockdown of COL3A1 significantly inhibited the migration, invasion, and EMT process of SHG44 and A172 cells.ConclusionsIn summary, our study demonstrated that collagen genes play an important role in regulating the immunosuppressive microenvironment and EMT process of glioma and could serve as potential therapeutic targets for glioma management.

Project description:This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide in vitro to elucidate cancer promoting gene signaling networks (GSNs) associated with As-transformed (B-As) cells. Following a six month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. As exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased ROS protection suggesting mitochondrial dysfunction. Carcinogenic initiation via ROS and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ GSN identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome GSN profile provide an in vitro As model for future lung cancer signaling research and data for chronic As exposure risk assessment. Whole genome expression profiling was conducted on arsenic (III) oxide-exposed human immortalized lung epithelial cells (BEAS-2B) following 6 month in vitro chronic exposure. As2O3 exposed cells (B-As) gene expression were compared to unexposed, passage control (B-Control) cell gene expression. Three B-As and four B-Control biological replicate cDNA samples were analyzed.

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Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay.

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Arsenic exposure perturbs epithelial-mesenchymal cell transition and gene expression in a collagen gel assay.

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