New targets of β-catenin signaling in the liver are involved in the glutamine metabolism
New targets of β-catenin signaling in the liver are involved in the glutamine metabolism
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DOI：
10.1038/sj.onc.1206118
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发表时间：
2002-11-28
期刊：
影响因子：
8
通讯作者：
Perret, C
中科院分区：
文献类型：
--
作者：
Cadoret, A;Ovejero, C;Perret, C
Wnt/β-连环蛋白信号的不适当激活与肝细胞癌（HCC）的发展有关，但β-连环蛋白的确切作用机制仍有待阐明。为了在体内鉴定肝脏中β-连环蛋白的靶基因，我们使用了抑制性消减杂交技术和在肝脏中表达活化的β-连环蛋白的转基因小鼠，这些小鼠发展成肝肿大。我们确定了三个基因参与谷氨酰胺代谢，编码谷氨酰胺合成酶（GS），鸟氨酸氨基转移酶（OAT）和谷氨酸转运蛋白GLT-1。通过北方印迹和免疫组织化学分析，我们证明这三个基因是由肝脏中β-连环蛋白通路的激活特异性诱导的。在不同的小鼠模型中，我们观察到这三个基因的显著上调，这些小鼠模型的肝脏中具有已知与肝细胞增殖相关的活化的β-连环蛋白信号传导。GS和GLT-1的细胞分布与β-连环蛋白活性平行。相比之下，在肝细胞增殖由信号独立的β-连环蛋白诱导的肝脏中没有观察到这三个基因的上调。此外，通过腺病毒载体介导的β-连环蛋白过表达，GS启动子在GS（+/LacZ）小鼠的肝脏中被激活。引人注目的是，人肝癌样本中GS基因的过表达与β-连环蛋白激活密切相关。总之，我们的结果表明GS是肝脏中Wnt/β-连环蛋白通路的靶点。由于谷氨酰胺途径与肝癌发生的联系已经被证实，我们提出β-连环蛋白对谷氨酰胺代谢的这三个基因的调节是肝癌发生的一个促成因素。
Inappropriate activation of the Wnt/beta-catenin signaling has been implicated in the development of hepatocellular carcinoma (HCC), but exactly how beta-catenin works remains to be elucidated. To identify, in vivo, the target genes of beta-catenin in the liver, we have used the suppression subtractive hybridization technique and transgenic mice expressing an activated beta-catenin in the liver that developed hepatomegaly. We identified three genes involved in glutamine metabolism, encoding glutamine synthetase (GS), ornithine aminotransferase (OAT) and the glutamate transporter GLT-1. By Northern blot and immunohistochemical analysis we demonstrated that these three genes were specifically induced by activation of the beta-catenin pathway in the liver. In different mouse models bearing an activated beta-catenin signaling in the liver known to be associated with hepatocellular proliferation we observed a marked up-regulation of these three genes. The cellular distribution of GS and GLT-1 parallels beta-catenin activity. By contrast no up-regulation of these three genes was observed in the liver in which hepatocyte proliferation was induced by a signal-independent of beta-catenin. In addition, the GS promoter was activated in the liver of GS(+/LacZ) mice by adenovirus vector-mediated beta-catenin overexpression. Strikingly, the overexpression of the GS gene in human HCC samples was strongly correlated with beta-catenin activation. Together, our results indicate that GS is a target of the Wnt/beta-catenin pathway in the liver. Because a linkage of the glutamine pathway to hepatocarcinogenesis has already been demonstrated, we propose that regulation of these three genes of glutamine metabolism by beta-catenin is a contributing factor to liver carcinogenesis.