Document Detail


Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.
MedLine Citation:
PMID:  22521957     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-13
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  261     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-21     Completed Date:  2012-07-23     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  204-16     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Inc.
Affiliation:
Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USA. tstueckle@hsc.wvu.edu
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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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