Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content

NIOSHTIC-2 Publications Search

Search Results

Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.

Authors
Stueckle-TA; Lu-Y; Davis-ME; Wang-L; Jiang-B-H; Holaskova-I; Schafer-R; Barnett-JB; Rojanasakul-Y
Source
Toxicol Appl Pharmacol 2012 Jun; 261(2):204-216
NIOSHTIC No.
20040762
Abstract
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-?B, MAPK and NCOR1 signaling disrupted PPAR?/?-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, EF1?, Akt, MAPK, and NF-?B 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.
Keywords
Arsenic-compounds; Exposure-levels; Carcinogens; Carcinogenesis; Lung-cells; Lung; Cancer; Genes; Author Keywords: Arsenic; Lung cancer; Carcinogenesis; Global gene expression; Ingenuity Pathway Analysis
Contact
Yon Rojanasakul, PO Box 9530, Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown,WV 26506
CODEN
TXAPA9
CAS No.
7440-38-2; 1327-53-3
Publication Date
20120601
Document Type
Journal Article
Email Address
yrojan@hsc.wvu.edu
Fiscal Year
2012
NTIS Accession No.
NTIS Price
Identifying No.
B05222012
Issue of Publication
2
ISSN
0041-008X
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Toxicology and Applied Pharmacology
State
WV; PA
TOP