Retinoid X receptor α enhances human cholangiocarcinoma growth through simultaneous activation of Wnt/β-catenin and nuclear factor-κB pathways

Retinoid X receptor alpha (RXR alpha) plays important roles in the malignancy of several cancers such as human prostate tumor, breast cancer, and thyroid tumor. However, its exact functions and molecular mechanisms in cholangiocarcinoma (CCA), a chemoresistant carcinoma with poor prognosis, remain unclear. In this study we found that RXR alpha was frequently overexpressed in human CCA tissues and CCA cell lines. Downregulation of RXRa led to decreased expression of mitosis-promoting factors including cyclin D1and cyclin E, and the proliferating cell nuclear antigen, as well as increased expression of cell cycle inhibitor p21, resulting in inhibition of CCA cell proliferation. Furthermore, RXR alpha knockdown attenuated the expression of cyclin D1 through suppression of Wnt/beta-catenin signaling. Retinoid X receptor alpha upregulated proliferating cell nuclear antigen expression through nuclear factor-kappa B (NF-kappa B) pathways, paralleled with downregulation of p21. Thus, the Wnt/beta-catenin and NF-kappa B pathways account for the inhibition of CCA cell growth induced by RXR alpha downregulation. Retinoid X receptor alpha plays an important role in proliferation of CCA through simultaneous activation of Wnt/beta-catenin and NF-kappa B pathways, indicating that RXR alpha might serve as a potential molecular target for CCA treatment.