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.
Highlights
Opisthorchis viverrini (Ov) infection has been recognized as a major cause of cholangiocarcinoma (CCA), a malignant tumor arising from the biliary tract epithelia which is a major public health problem in northeast Thailand, where the highest prevalence of CCA in the world is reported (Sithithaworn and HaswellElkins, 2003; Sripa et al, 2007)
The present study examined whether the alteration of PI3K/AKT/PTEN and Wnt/β-catenin signaling pathway occured during Ov-induced CCA carcinogenesis in a hamster model
Several studies have demonstrated that alteration of PI3K/AKT/PTEN and Wnt/ β-catenin was found in many cancers and these pathways may serve as the potential targets for cancer treatment (Gong et al, 2012; Pandurangan, 2013; Jannesari-Ladani et al, 2014; Tan et al, 2014)
Summary
Opisthorchis viverrini (Ov) infection has been recognized as a major cause of cholangiocarcinoma (CCA), a malignant tumor arising from the biliary tract epithelia which is a major public health problem in northeast Thailand, where the highest prevalence of CCA in the world is reported (Sithithaworn and HaswellElkins, 2003; Sripa et al, 2007). To identify the candidate genes underlying Ov-induced CCA, we have previously investigated candidate genes that may underly Ov and NDMA-induced CCA in a hamster animal model and found that 1 downregulated and 23 upregulated transcripts are involved in CCA development (Loilome et al, 2006). The signal transduction protein kinase A regulatory subunit Iα (Prkar1a) has been observed to be involved in CCA development and progression (Loilome et al, 2006). Prkar1a inhibition lead to apoptosis in CCA cells together with a decrease in several protein kinase pathways, including PI3K/AKT, Wnt/β-catenin, JAK/STAT and MAPK signaling (Loilome et al, 2011). We have reported multiple kinases that are activated in both CCA cell lines and human CCA tissues, including the PI3K/ AKT, Wnt/β-catenin, JAK/STAT and MAPK signaling pathways (Dokduang et al, 2013).
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