title: Opisthorchis viverrini infection activates the PI3K/ AKT/PTEN and Wnt/β-catenin signaling pathways in a Cholangiocarcinogenesis model.
abstract: Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and Wnt/β- catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/ AKT/PTEN and Wnt/β-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the p85α-regulatory and p110α-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of Wnt/β-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and β-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of β-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and Wnt/β-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand E-mail : watloi@yahoo.com.
authors.forename: Supak
authors.initials: S
authors.lastname: Yothaisong
authors.forename: Malinee
authors.initials: M
authors.lastname: Thanee
authors.forename: Nisana
authors.initials: N
authors.lastname: Namwat
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
authors.forename: Thidarut
authors.initials: T
authors.lastname: Boonmars
authors.forename: Anucha
authors.initials: A
authors.lastname: Puapairoj
authors.forename: Watcharin
authors.initials: W
authors.lastname: Loilome
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000469:parasitology; D063646:Carcinogenesis / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000469:parasitology; D006224:Cricetinae; D004195:Disease Models, Animal; D009889:Opisthorchiasis / Q000378:metabolism* / Q000469:parasitology; D009891:Opisthorchis; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013785:Thailand; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase