5916

RARG

retinoic acid receptor, gamma;RARG;retinoic acid receptor, gamma

RAR-gamma|nuclear receptor subfamily 1 group B member 3|retinoic acid nuclear receptor gamma variant 1|retinoic acid nuclear receptor gamma variant 2|retinoic acid receptor gamma

12q13

protein-coding

Aberrant expression and function of retinoic acid receptor gamma (RARgamma) are often involved in the progression of several cancers. However, the role of RARgamma in cholangiocarcinoma (CCA), chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In the present study, we found that RARgamma 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 RARgamma reduced CCA cell proliferation, migration, invasion, and colony formation ability in vitro and tumorigenic potential in nude mice. RARgamma knockdown resulted in upregulation of cell cycle inhibitor P21, as well as downregulation of cyclin D1, proliferating cell nuclear antigen, and matrix metallopeptidase 9, in parallel with suppression of the Akt/NF-kappaB pathway. Furthermore, overexpression of RARgamma 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 RARgamma interacted with beta-catenin and led to beta-catenin nuclear translocation. Taken together, our results suggested that RARgamma plays an important role in the proliferation, metastasis, and chemoresistance of CCA through simultaneous activation of the Akt/NF-kappaB and Wnt/beta-catenin pathways, serving as a potential molecular target for CCA treatment.