title: Apoptosis of cholangiocytes modulated by thioredoxin of carcinogenic liver fluke.
abstract: Chronic infection with the food-borne liver fluke, Opisthorchis viverrini, frequently induces cancer of the bile ducts, cholangiocarcinoma. Opisthorchiasis is endemic in Thailand, Lao PDR, Cambodia and Vietnam, where eating undercooked freshwater fish carrying the juvenile stage of this pathogen leads to human infection. Because inhibition of apoptosis facilitates carcinogenesis, this study investigated modulation by thioredoxin from O. viverrini of apoptosis of bile duct epithelial cells, cholangiocytes. Cells of a cholangiocyte line were incubated with the parasite enzyme after which they were exposed hydrogen peroxide. Oxidative stress-induced apoptosis was monitored using flow cytometry, growth in real time and imaging of living cells using laser confocal microscopy. Immunolocalization revealed liver fluke thioredoxin within cholangiocytes. Cells exposed to thioredoxin downregulated apoptotic genes in the mitogen activated protein kinases pathway and upregulated anti-apoptosis-related genes including apoptosis signaling kinase 1, caspase 9, caspase 8, caspase 3, survivin and others. Western blots of immunoprecipitates of cell lysates revealed binding of thioredoxin to apoptosis signaling kinase 1. Together the findings indicated that thioredoxin from O. viverrini inhibited oxidative stress-induced apoptosis of bile duct epithelial cells, which supports a role for this liver fluke oxidoreductase in opisthorchiasis-induced cholangiocarcinogenesis.
authors.affiliation: Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand; WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Laboratory, Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA.
authors.forename: Pitchaya
authors.initials: P
authors.lastname: Matchimakul
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Parasite Genomics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rinaldi
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA; Department of Microbiology, Faculty of Science, Mahidol University, Rachthewee, Bangkok 10400, Thailand.
authors.forename: Sutas
authors.initials: S
authors.lastname: Suttiprapa
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA.
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Mann
authors.affiliation: Center for Microscopy & Image Analysis, and Department of Anatomy & Regenerative Biology, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA.
authors.forename: Anastas
authors.initials: A
authors.lastname: Popratiloff
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Thewarach
authors.initials: T
authors.lastname: Laha
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA.
authors.forename: Rafael N
authors.initials: RN
authors.lastname: Pimenta
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Cochran
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Sasithorn
authors.initials: S
authors.lastname: Kaewkes
authors.affiliation: WHO Collaborating Centre for Research and Control of Opisthorchiasis (Southeast Asian Liver Fluke Disease), Tropical Disease Research Laboratory, Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: banchob@kku.ac.th.
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.affiliation: Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC 20037, USA. Electronic address: pbrindley@gwu.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brindley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001652:Bile Ducts / Q000469:parasitology* / Q000473:pathology*; D002460:Cell Line; D006801:Humans; D051379:Mice; D009889:Opisthorchiasis / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D009891:Opisthorchis / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D013879:Thioredoxins
keywords: Apoptosis; Apoptosis signal-regulating kinase-1; Carcinogenesis; Cholangiocyte; Gene arrays; Liver fluke; Opisthorchis viverrini; Oxidative stress; Thioredoxin; xCELLigence