The oncofetal gene glypican 3 is regulated in the postnatal liver by zinc fingers and homeoboxes 2 and in the regenerating liver by alpha-fetoprotein regulator 2
The oncofetal gene glypican 3 is regulated in the postnatal liver by zinc fingers and homeoboxes 2 and in the regenerating liver by alpha-fetoprotein regulator 2
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DOI：
10.1002/hep.21825
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发表时间：
2007-11-01
期刊：
影响因子：
13.5
通讯作者：
Spear, Brett T.
中科院分区：
文献类型：
--
作者：
Morford, Lorri A.;Davis, Christina;Spear, Brett T.
磷脂酰肌醇蛋白聚糖3（Gpc 3）基因在胎儿肝脏中大量表达，在正常成人肝脏中无活性，在肝细胞癌（H-CC）中经常重新激活。这种在HCC中的再激活导致了对Gpc 3作为诊断肿瘤标志物及其在肿瘤发生中的可能作用的相当大的兴趣。尽管有这种兴趣，但人们对Gpc 3监管的基础知之甚少。基于Gpc 3和甲胎蛋白在肝脏中表达的相似性，我们推断共同的因素可能调节这两个基因。在这里，我们确定锌指和同源异型盒2（Zhx 2）作为Gpc 3的调节器。成年肝脏Gpc 3信使RNA水平的小鼠品系特异性差异和转基因小鼠研究表明，Zhx 2抑制Gpc 3在成年肝脏中的表达。我们还表明，Gpc 3在四氯化碳处理后的再生肝脏中被激活，并且Gpc 3诱导的水平由甲胎蛋白调节因子2（Afr 2）控制。结论：我们发现，Zhx 2作为一个阻遏物的Gpc 3在成人肝脏，这提出了一个有趣的可能性，Zhx 2也可能参与Gpc 3在肝癌的再激活。我们还表明，Gpc 3在再生肝脏中以Afr 2依赖的方式被激活。Zhx 2和Afr 2代表Gpc 3的第一个已知调节子。
The Glypican 3 (Gpc3) gene is expressed abundantly in the fetal liver, is inactive in the normal adult liver, and is frequently reactivated in hepatocellular carcinoma (H-CC). This reactivation in HCC has led to considerable interest in Gpc3 as a diagnostic tumor marker and its possible role in tumorigenesis. Despite this interest, the basis for Gpc3 regulation is poorly understood. On the basis of the similarities between Gpc3 and alpha-fetoprotein expression in the liver, we reasoned that common factors might regulate these 2 genes. Here we identify zinc fingers and homeoboxes 2 (Zhx2) as a regulator of Gpc3. Mouse strain-specific differences in adult liver Gpc3 messenger RNA levels and transgenic mouse studies indicate that Zhx2 represses Gpc3 expression in the adult liver. We also demonstrate that Gpc3 is activated in the regenerating liver following a carbon tetrachloride treatment and that the level of Gpc3 induction is controlled by alpha-fetoprotein regulator 2 (Afr2). Conclusion: We show that Zhx2 acts as a repressor of Gpc3 in the adult liver, and this raises the interesting possibility that Zhx2 might also be involved in Gpc3 reactivation in HCC. We also show that Gpc3 is activated in the regenerating liver in an Afr2-dependent manner. Zhx2 and Afr2 represent the first known regulators of Gpc3.