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Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

  • Yothaisong, Supak (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Thanee, Malinee (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Namwat, Nisana (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Yongvanit, Puangrat (Department of Biochemistry, Faculty of Medicine, Khon Kaen University) ;
  • Boonmars, Thidarut (Department of Parasitology, Faculty of Medicine, Khon Kaen University) ;
  • Puapairoj, Anucha (Department of Pathology, Faculty of Medicine, Khon Kaen University) ;
  • Loilome, Watcharin (Department of Biochemistry, Faculty of Medicine, Khon Kaen University)
  • Published : 2015.01.06

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 $Wnt/{\beta}$-catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/AKT/PTEN and $Wnt/{\beta}$-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 $p85{\alpha}$-regulatory and $p110{\alpha}$-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 $Wnt/{\beta}$-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and ${\beta}$-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of ${\beta}$-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 $Wnt/{\beta}$-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.

Keywords

Opisthorchis viverrini;PI3K/AKT/PTEN;$Wnt/{\beta}$-catenin;cholangiocarcinoma

Acknowledgement

Supported by : Thailand Research Fund

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