title: Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells.
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-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.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USA. tstueckle@hsc.wvu.edu
authors.forename: Todd A
authors.initials: TA
authors.lastname: Stueckle
authors.forename: Yongju
authors.initials: Y
authors.lastname: Lu
authors.forename: Mary E
authors.initials: ME
authors.lastname: Davis
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
authors.forename: Ida
authors.initials: I
authors.lastname: Holaskova
authors.forename: Rosana
authors.initials: R
authors.lastname: Schafer
authors.forename: John B
authors.initials: JB
authors.lastname: Barnett
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004847:Epithelial Cells; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009361:Neoplasm Invasiveness; D016273:Occupational Exposure / Q000009:adverse effects*; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000633:toxicity*; D047493:PPAR alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001152:Arsenicals; D010087:Oxides; D047493:PPAR alpha; D000077237:Arsenic Trioxide