Oncogenic Activity of Retinoic Acid Receptor γ Is Exhibited through Activation of the Akt/NF-κB and Wnt/β-Catenin Pathways in Cholangiocarcinoma

Aberrant expression and function of retinoic acid receptor gamma (RAR gamma) are often involved in the progression of several cancers. However, the role of RAR gamma in cholangiocarcinoma (CCA), chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In the present study, we found that RAR gamma was frequently overexpressed in human CCA specimens. Its overexpression was associated with poor differentiation, lymph node metastasis, high serum carbohydrate antigen 19-9 level, and poor prognosis of CCA. Downregulation of RAR gamma reduced CCA cell proliferation, migration, invasion, and colony formation ability in vitro and tumorigenic potential in nude mice. RAR gamma knockdown resulted in upregulation of cell cycle inhibitor P21, as well as down-regulation of cyclin D1, proliferating cell nuclear antigen, and matrix metallopeptidase 9, in parallel with suppression of the Akt/NF-kappa B pathway. Furthermore, overexpression of RAR gamma contributed to the multidrug chemoresistance of CCA cells, at least in part due to upregulation of P glycoprotein via activation of the Wnt/beta-catenin pathway. Molecular mechanism studies revealed that RAR gamma interacted with beta-catenin and led to beta-catenin nuclear translocation. Taken together, our results suggested that RAR gamma plays an important role in the proliferation, metastasis, and chemoresistance of CCA through simultaneous activation of the Akt/NF-kappa B and Wnt/beta-catenin pathways, serving as a potential molecular target for CCA treatment.