The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of β-catenin signaling pathway.
The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of β-catenin signaling pathway.
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DOI：
10.1093/carcin/bgab099
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发表时间：
2022-04-25
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
已有研究表明，维甲酸X受体α(RXRα)的磷酸化与肝细胞癌的发生发展有关。然而，这些发现是在表达磷酸化RXRα(p-RXRα)蛋白的肝癌细胞系中发现的；因此，目前尚不清楚p-RXRα是否影响体内肝癌的发生。因此，为了研究p-rxrα在体内的生物学功能，我们建立了多西环素诱导的ES细胞系和转基因小鼠，它们都以多西环素依赖的方式过表达rxrα的磷酸化突变体T82D/S260D。我们发现，在二乙基亚硝胺(DEN)处理的T82D/S260D诱导的小鼠中，肝脏肿瘤的发展，特别是高级别腺瘤和肝癌的发展被促进。此外，转基因小鼠肝脏肿瘤发生率的增加可归因于促进细胞周期进程。有趣的是，在DEN处理的T82D/S260D诱导的小鼠肝肿瘤中，β-连环蛋白及其靶基因细胞周期蛋白D1的表达增加，同时细胞质和核的β-连环蛋白的表达增加，表明其稳定和转录激活。这些结果表明，p-RXRα通过激活β-连环蛋白信号通路促进DEN诱导的小鼠肝癌的发生，提示p-RXRα可能是治疗肝癌的一个可能的靶点。P-RXRα在化学诱导的小鼠肝癌发生中起关键作用。RxRα的异常磷酸化参与了体内肝细胞癌的发生，提示p-rxrα有可能成为治疗肝癌的靶点。
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. 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.
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影响因子：
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