Open AccessThe phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of β-catenin signaling pathway
Author(s) -
Hidetaka Sakai,
Yoshihiko Yamada,
Minoru Kubota,
Kenji Imai,
Yohei Shirakami,
Hiroyuki Tomita,
Akira Hara,
Masahito Shimizu
Publication year - 2021
Publication title -
carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.688
H-Index - 204
eISSN - 1460-2180
pISSN - 0143-3334
DOI - 10.1093/carcin/bgab099
Subject(s) - retinoid x receptor , cancer research , retinoid , biology , cyclin d1 , phosphorylation , retinoid x receptor alpha , catenin , signal transduction , cell cycle , chemistry , microbiology and biotechnology , cell culture , nuclear receptor , transcription factor , wnt signaling pathway , cell , retinoic acid , biochemistry , gene , genetics
Previous studies have shown that phosphorylation of the retinoid X receptor-α (RXRα) is associated with the development of hepatocellular carcinoma (HCC). However, these findings were revealed using HCC cell lines that express phosphorylated-RXRα (p-RXRα) proteins; therefore, it remains unclear whether p-RXRα affects hepatocarcinogenesis in vivo. Therefore, to investigate the biological function of p-RXRα in vivo, we developed a doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress the phosphomimetic mutant form of RXRα, T82D/S260D, in a doxycycline-dependent manner. We found that the development of liver tumors, especially high-grade adenoma and HCC, was enhanced in diethylnitrosamine (DEN)-treated T82D/S260D-inducible mice. Moreover, the increased incidence of liver tumors in the transgenic mice was attributable to the promotion of cell cycle progression. Interestingly, the expression of β-catenin protein and its target gene cyclin D1 was elevated in the liver tumors of DEN-treated T82D/S260D-inducible mice, concurrent with increased cytoplasmic and nuclear β-catenin protein expression, indicating its stabilization and transcriptional activation. These results indicate that p-RXRα promotes DEN-induced hepatocarcinogenesis in mice through the activation of the β-catenin signaling pathway, suggesting that p-RXRα may serve as a possible therapeutic target for HCC.