Abstract 2709: The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice

Abstract

Abstract We have reported that a malfunction of RXRα due to aberrant phosphorylation at serine 260 by MAPK is associated with the development of hepatocellular carcinoma (HCC) (Cancer Res 2001). The phosphorylated RXRα impairs normal receptor functions of either RXR or RAR, which are respective homodimeric or heterodimeric partner of RXRα, in a dominant-negative manner. Besides, these impaired receptor functions result in the downregulation of their target gene expression and inducing hepatocarcinogenesis by promoting cell proliferation and the inhibition of apoptosis, which suggesting that phosphorylated RXRα plays a crucial role in the development of HCC. However, these findings were revealed primarily using HCC cell lines that express the phosphorylated-RXRα (p-RXRα) proteins and it still remains unclear whether p-RXRα may impact in the process of hepatocarcinogenesis in vivo. Therefore, in order to investigate the biological functions of the p-RXRα in vivo, we generated doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress phosphomimic mutant of RXRα (T82D/S260D). We found that the T82D/S260D inducible ES cells kept undifferentiated state in differentiating media, which indicating that the phosphorylated form of RXRα plays an important role to maintain pluripotency of ES cells. On the other hand, the development of liver tumors induced by liver carcinogen diethylnitrosamine (DEN) was enhanced in the transgenic mice that overexpress T82D/S260D protein in the liver. Besides, the increased liver tumors in the transgenic mice resulted from the promotion of cell cycle progression, not the inhibition of apoptosis. Interestingly, expression of β-catenin and its target genes, cyclin D1 and c-myc, were increased in transgenic liver tumors, although the expression of retinoid-related genes, such as RARβ, p21 and p27, were not altered compared with control mice. These results suggest that a retinoid nuclear receptor, RXRα may prevent the development of DEN-induced liver tumors by regulating the canonical Wnt/β-catenin signaling pathways in mice. Citation Format: Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu. The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2709. doi:10.1158/1538-7445.AM2015-2709