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Pregnane X receptor inhibits the transdifferentiation of hepatic stellate cells by down-regulating periostin expression.
Biochemical Journal ( IF 4.4 ) Pub Date : 2024-09-18 , DOI: 10.1042/bcj20240172
Takumi Sato 1 , Ryota Shizu 1 , Ryonosuke Baba 1 , Akira Ooka 1 , Takuomi Hosaka 1 , Yuichiro Kanno 1 , Kouichi Yoshinari 1
Affiliation  

Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that plays a key role in drug metabolism. Recently, PXR was found to attenuate the development of liver cancer by suppressing epithelial-mesenchymal transition (EMT) in liver cancer cells in a mouse model of two-stage chemical carcinogenesis. To elucidate the role of PXR in the EMT of liver cancer cells, we focused on its role in hepatic stellate cells (HSCs), which are components of the tumor microenvironment in hepatocellular carcinoma (HCC). Human HSC-derived LX-2 cells stably expressed destabilization domain (DD)-fused human PXR (hPXR-LX2 cells). Human HCC-derived HepG2 cells were transfected with the EMT marker VIM promoter-regulated reporter plasmid and co-cultured with hPXR-LX2 cells or treated with hPXR-LX2-derived conditioned medium (CM). Co-culture or CM treatment increased reporter activity in HepG2 cells. This induction was attenuated upon PXR activation in hPXR-LX2 cells by treatment with the DD-stabilizing chemical Shield-1 and the human PXR ligand rifampicin. PXR activation in hPXR-LX2 cells exhibited inhibition of TGF-β1-induced transdifferentiation, supported by observations of morphological changes and protein or mRNA levels of the transdifferentiation markers COL1A1 and FN1. PXR activation in hPXR-LX2 cells also attenuated the mRNA levels of the key transdifferentiation factor, POSTN. Treatment of hPXR-LX2 cells with recombinant POSTN restored the PXR-mediated suppression of transdifferentiation. Reporter assays with the POSTN promoter showed that PXR inhibited the NF-κB-mediated transcription of POSTN. Consequently, PXR activation in HSCs is expected to inhibit transdifferentiation by down-regulating POSTN expression, thereby suppressing EMT of liver cancer cells.

中文翻译:


Pregnane X 受体通过下调骨膜素表达来抑制肝星状细胞的转分化。



孕烷 X 受体 (PXR) 是一种异生素感应核受体,在药物代谢中发挥关键作用。最近,在两阶段化学癌变小鼠模型中,发现 PXR 通过抑制肝癌细胞的上皮-间质转化 (EMT) 来减轻肝癌的发展。为了阐明 PXR 在肝癌细胞 EMT 中的作用,我们重点关注其在肝星状细胞 (HSC) 中的作用,肝星状细胞是肝细胞癌 (HCC) 肿瘤微环境的组成部分。人 HSC 衍生的 LX-2 细胞稳定表达融合去稳定结构域 (DD) 的人 PXR(hPXR-LX2 细胞)。人 HCC 来源的 HepG2 细胞用 EMT 标记 VIM 启动子调节的报告质粒转染,并与 hPXR-LX2 细胞共培养或用 hPXR-LX2 来源的条件培养基 (CM) 处理。共培养或 CM 处理增加了 HepG2 细胞中的报告基因活性。通过用 DD 稳定化学物质 Shield-1 和人 PXR 配体利福平处理,hPXR-LX2 细胞中 PXR 激活后,这种诱导作用减弱。 hPXR-LX2 细胞中的 PXR 激活表现出对 TGF-β1 诱导的转分化的抑制,这得到了转分化标记物 COL1A1 和 FN1 的形态变化以及蛋白质或 mRNA 水平观察的支持。 hPXR-LX2 细胞中的 PXR 激活也减弱了关键转分化因子 POSTN 的 mRNA 水平。用重组 POSTN 处理 hPXR-LX2 细胞恢复了 PXR 介导的转分化抑制。 POSTN 启动子的报告基因检测表明 PXR 抑制 NF-κB 介导的 POSTN 转录。因此,HSC 中的 PXR 激活有望通过下调 POSTN 表达来抑制转分化,从而抑制肝癌细胞的 EMT。
更新日期:2024-08-22
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