Cholangiocarcinoma is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of cholangiocarcinoma 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 cholangiocarcinoma.  Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic cholangiocarcinoma. 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 cholangiocarcinoma. There is an upregulation 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 cholangiocarcinoma, 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 miRNAs, PI3K/AKT/PTEN/GSK-3β, retinoic acid receptors, dickkopf-1, PRKAR1A/PKAI, SLAP, LKB1 and CXCR4. The selective inhibitors of Wnt/β-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal cholangiocarcinoma. The present review discusses the role of Wnt/β-catenin along with its relation with other signaling pathways in the induction and progression of cholangiocarcinoma.

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