Abstract
Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of CCA is generally poor due to its diagnosis at the late stages. The currently employed chemotherapeutic agents do not increase the survival rate in patients with unresectable CCA. Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic CCA. Clinical as well as preclinical studies have suggested the key role of the activation of Wnt/β-catenin signaling pathway in the induction and progression of CCA. There is an up-regulation of different Wnt ligands including Wnt2, Wnt3, Wnt5, Wnt7 and Wnt10 along with redistribution of β-catenin (more expression in the nucleus and lesser on the cell surface due to nuclear translocation of β-catenin) in different types of malignant biliary tumors. Apart from the role of this pathway in the induction and progression of CCA, this pathway is also involved in inducing multidrug resistance by inducing the expression of P-glycoprotein efflux pump on the cancer cells. These deleterious effects of Wnt/β-catenin signaling are mediated in association with other signaling pathways involving microRNAs (miRNAs), PI3K/AKT/PTEN/GSK-3β, retinoic acid receptors (RARs), dickkopf-1 (DKK1), protein kinase A regulatory subunit 1 α (PRKAR1A/PKAI), (SLAP), liver kinase B1 (LKB1) and CXCR4. The selective inhibitors of Wnt/β-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal CCA. The present review discusses the role of Wnt/β-catenin along with its relation with other signaling pathways in the induction and progression of CCA.
Highlights
Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts
Exposure of cholangiocytes to Increase in nuclear translocation of Epithelial growth factor contributes to Claperon et al, 2014 epithelial growth factor β-catenin and disruption of adherens CCA by inducing epithelial–mesenchymal transition (EMT) through junctions β-catenin
The interrelationship between GSK-3β/β-catenin has been described in the development of multidrug resistance in CCA and it is shown that Wnt3a activates GSK-3β/β-catenin signaling to up-regulate the expression of P-glycoprotein efflux pump on the tumor cells [42]
Summary
Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The study by Mao et al [40] described that fascin promotes EMT of CCA cells by increasing the nuclear and decreasing the plasma membrane localization of β-catenin. The administration of β-escin was shown to abolish multidrug resistance in CCA cells by inducing degradation of β-catenin and down-regulating the expression of P-glycoprotein [42] again suggesting the importance of Wnt/β-catenin signaling in inducing drug resistance in CCA (Table 2).
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