Abstract 4052: The role of the phosphorylated RXRα on diethylnitrosamine-induced liver tumorigenesis in mice

Abstract

Abstract We have previously reported that a malfunction of RXRα due to aberrant phosphorylation at serine 260 by MAPK is associated with the development of hepatocellular carcinoma (HCC). 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 stimulating cell proliferation and inhibiting apoptosis, 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 p-RXRα on hepatocarcinogenesis in vivo, we generated doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress phosphomimic mutant of RXRα (T82D/S260D). Interestingly, the transcriptional activities of Retinoid X Receptor Response Element (RXRE) were significantly reduced in the Mouse Embryonic Fibroblasts (MEFs) derived from the transgenic mice, suggesting that the retinoid signaling via RXRα were impaired in the mice. Moreover, 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. Notably, 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 the phospho-modification of RXRα may promote the development of DEN-induced liver tumors through the activation of β-catenin signaling pathways in mice. Citation Format: Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu. The role of the phosphorylated RXRα on diethylnitrosamine-induced liver tumorigenesis in mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4052.