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The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of β-catenin signaling pathway.
- Source :
-
Carcinogenesis [Carcinogenesis] 2022 Apr 25; Vol. 43 (3), pp. 254-263. - Publication Year :
- 2022
-
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.<br /> (© The Author(s) 2021. Published by Oxford University Press.)
- Subjects :
- Animals
Carcinogenesis chemically induced
Carcinogenesis genetics
Diethylnitrosamine toxicity
Doxycycline
Mice
Mice, Transgenic
Retinoid X Receptor alpha genetics
Retinoid X Receptor alpha metabolism
Retinoid X Receptors
Signal Transduction
beta Catenin genetics
beta Catenin metabolism
Carcinoma, Hepatocellular chemically induced
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular metabolism
Liver Neoplasms chemically induced
Liver Neoplasms genetics
Liver Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 43
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 34668523
- Full Text :
- https://doi.org/10.1093/carcin/bgab099