Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis
Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis
复制标题
DOI：
10.1093/carcin/bgq277
复制
发表时间：
2011-04-01
期刊：
影响因子：
4.7
通讯作者：
Mori, Masatomo
中科院分区：
文献类型：
--
作者：
Takizawa, Daichi;Kakizaki, Satoru;Mori, Masatomo
核受体组成型活性/雄烷受体（CAR）作为来自内源性代谢和外源性化学物质的毒性副产物的传感器。我们先前报道了CAR通过上调脂质过氧化作用在非酒精性脂肪性肝炎（NASH）饮食模型中加重肝损伤和纤维化。在这项研究中，我们研究了CAR在NASH模型中肝细胞癌发展中的病理作用。CAR（+/+）和CAR（-/-）小鼠在肿瘤发生后，在2周龄时单次给予遗传毒性致癌物二乙基亚硝胺（DEN），饲喂蛋氨酸和胆碱缺乏（MCD）饲料。有趣的是，MCD饮食显着促进了CAR（+/+）小鼠中DEN诱导的肝癌发生。然而，CAR的缺失导致显著较低的肿瘤发生率和较小的肿瘤直径。与MCD处理的CAR（-/-）小鼠相比，MCD处理的CAR（+/+）小鼠的肝细胞显示出Ki-67（细胞增殖的标志物）的染色频率显著更高，并显示出c-Myc和FoxM 1转录物的表达更高。免疫组织化学显示CAR的核转位，因此表明喂食MCD饲料的CAR（+/+）小鼠肝细胞中CAR信号传导的活化增加。此外，使用具有TCPOBOP的CAR稳定表达细胞系的体外实验表明CAR活化直接导致细胞增殖。与CAR（-/-）小鼠相比，喂食MCD饲料的CAR（+/+）小鼠的存活率显著较低。总之，这些结果表明CAR可能因此通过上调细胞增殖在鼠NASH模型的肝癌发生中起关键作用。
The nuclear receptor constitutive active/androstane receptor (CAR) acts as a sensor of toxic byproducts derived from the endogenous metabolism and exogenous chemicals. We previously reported that CAR is responsible for exacerbating hepatic injury and fibrosis in a dietary model of non-alcoholic steatohepatitis (NASH) via upregulation of lipid peroxidation. In this study, we investigated the pathological roles of the CAR in the development of hepatocellular carcinoma in NASH model. CAR(+/+) and CAR(-/-) mice were fed methionine- and choline-deficient (MCD) diet after tumor initiation with a single dose of the genotoxic carcinogen diethylnitrosamine (DEN) at 2 weeks of age. Interestingly, the MCD diet dramatically promoted DEN-induced hepatocarcinogenesis in CAR(+/+) mice. However, the deletion of CAR leads to a significantly lower tumor incidence and smaller tumor diameter. Hepatocytes of MCD-treated-CAR(+/+) mice showed a significantly higher staining frequency of Ki-67, a marker of cell proliferation, and exhibited a higher expression of c-Myc and FoxM1 transcripts compared with MCD-treated CAR(-/-) mice. Immunohistochemistry revealed the nuclear translocation of CAR thus suggesting that the activation of CAR signaling increased in the hepatocytes of CAR(+/+) mice fed MCD diet. In addition, in vitro experiments using the CAR stably expressed cell line with TCPOBOP have suggested that CAR activation directly leads to cell proliferation. Survival was significantly lower in the CAR(+/+) mice fed the MCD diet in comparison with the CAR(-/-) mice. Taken together, these results suggest that CAR may therefore play a critical role in the hepatocarcinogenesis of the murine NASH model via the upregulation of cell proliferation.