The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of β-catenin signaling pathway. (20th October 2021)

• Record Type: Journal Article
• Authors: Sakai, Hiroyasu; Yamada, Yasuhiro; Kubota, Masaya; Imai, Kenji; Shirakami, Yohei; Tomita, Hiroyuki; Hara, Akira; Shimizu, Masahito
• Is Part Of: Carcinogenesis. Volume 43:Number 3(2022)
• Page Start: 254
• Page End: 263
• Publication Date: 2021-10-20
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgab099
• Languages: English
• ISSNs: 0143-3334

Abstract

Abstract: 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. Abstract : p-RXRα plays a key role in chemically induced hepatocarcinogenesis in mice. The fact that the abnormal phosphorylation of RXRα is involved in liver carcinogenesis in vivo suggests that p-RXRα may serve as a possible therapeutic target for HCC.