| Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. | |
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MedLine Citation:
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PMID: 22521957 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month 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. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species 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' gene signaling network 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 expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. |
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Authors:
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Todd A Stueckle; Yongju Lu; Mary E Davis; Liying Wang; Bing-Hua Jiang; Ida Holaskova; Rosana Schafer; John B Barnett; Yon Rojanasakul |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-13 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 261 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-05-21 Completed Date: 2012-07-23 Revised Date: 2013-06-06 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 204-16 Citation Subset: IM |
Copyright Information:
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Published by Elsevier Inc. |
Affiliation:
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Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USA. tstueckle@hsc.wvu.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arsenicals Cell Proliferation / drug effects Cell Transformation, Neoplastic* Cells, Cultured Epithelial Cells Female Gene Regulatory Networks / drug effects* Humans Lung Lung Neoplasms / chemically induced*, pathology Mice Mitochondria / drug effects, physiology Neoplasm Invasiveness Occupational Exposure / adverse effects* Oligonucleotide Array Sequence Analysis Oxides / toxicity* PPAR alpha / metabolism Signal Transduction / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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P20RR016477/RR/NCRR NIH HHS; R01 HL095579/HL/NHLBI NIH HHS; R01-HL076340/HL/NHLBI NIH HHS; R01-HL076340-04S1/HL/NHLBI NIH HHS; R01-HL095579/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Arsenicals; 0/Oxides; 0/PPAR alpha; 1327-53-3/arsenic trioxide |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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