title: CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment.
abstract: Expression of CD44, especially the variant isoforms (CD44v) of this major cancer stem cell marker, contributes to reactive oxygen species (ROS) defense through stabilizing xCT (a cystine-glutamate transporter) and promoting glutathione synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of CD44v in the regulation of the ROS defense system in cholangiocarcinoma (CCA). Immunohistochemical staining of CD44v and p38(MAPK) (a major ROS target) expression in Opisthorchis viverrini-induced hamster CCA tissues (at 60, 90, 120, and 180 days) reveals a decreased phospho-p38(MAPK) signal, whereas the CD44v signal was increased during bile duct transformation. Patients with CCA showed CD44v overexpression and negative-phospho-p38(MAPK) patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38(MAPK) patients (P = 0.030). Knockdown of CD44 showed that xCT and glutathione levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v cancer stem cell therapy using sulfasalazine. Glutathione decreased and ROS increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of CD44v leads to the suppression of p38(MAPK) in transforming bile duct cells. The redox status regulation of CCA cells depends on the expression of CD44v to contribute the xCT function and is a link to the poor prognosis of patients. Thus, an xCT inhibitor could inhibit cell growth and activate cell death. This suggests that an xCT-targeting drug may improve CCA therapy by sensitization to the available drug (e.g. gemcitabine) by blocking the mechanism of the cell's ROS defensive system.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Malinee
authors.initials: M
authors.lastname: Thanee
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Watcharin
authors.initials: W
authors.lastname: Loilome
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Techasen
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan.|Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Nisana
authors.initials: N
authors.lastname: Namwat
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Narong
authors.initials: N
authors.lastname: Khuntikeo
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Attapol
authors.initials: A
authors.lastname: Titapun
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Chawalit
authors.initials: C
authors.lastname: Pairojkul
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005210:Fasciola hepatica / Q000472:pathogenicity*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018960:Hyaluronan Receptors; D017382:Reactive Oxygen Species; D012460:Sulfasalazine; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CD44v; cholangiocarcinoma; opisthorchiasis; redox status; sulfasalazine