Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma
Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma
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DOI：
10.1038/labinvest.2011.123
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发表时间：
2011-11-01
影响因子：
5
通讯作者：
Bosserhoff, Anja-Katrin
中科院分区：
文献类型：
--
作者：
Maegdefrau, Ulrike;Arndt, Stephanie;Bosserhoff, Anja-Katrin
最近，我们发现骨形态发生蛋白（BMP）4在肝细胞癌（HCC）中增加。此外，最近的报道描述了BMP，特别是BMP 6，作为铁调素表达在铁稳态中的重要调节剂。因此，我们的目的是阐明为什么在HCC患者中BMP表达增强不会导致铁代谢的严重变化。对BMP 4和BMP 6表达模式的初步分析显示，与原代人肝细胞（PHH）和正常肝组织相比，HCC细胞系和组织样品中的mRNA和蛋白水平表达增强。然而，有趣的是，在HCC细胞系和组织中，铁调素表达降低。BMP 6受体表达分析显示HCC中BMP 6特异性受体亚单位丢失。为了确定一个可能的调节机制，导致缺乏对BMP 4的反应，我们分析了血幼素（HJV）的表达，这是参与铁代谢的BMP辅助受体。HJV在HCC细胞系和组织中的表达显著降低。HJV启动子分析揭示了潜在的HNF-1 α和snail结合位点，但功能分析排除了这些转录调节因子或启动子甲基化是HCC中HJV下调的原因。然而，我们在HJV 3 '-非翻译区鉴定了富含AU的元件，并揭示了与PHH相比，HCC细胞中HJV mRNA的衰减明显更快，表明mRNA稳定性降低是HCC中HJV表达丧失的原因。实验室调查（2011）91，1615-1623; doi：10.1038/labinvest.2011.123;在线发表2011年8月22日
Recently, we revealed that bone morphogenetic protein (BMP) 4 is increased in hepatocellular carcinoma (HCC). Furthermore, latest reports described BMPs, in particular BMP6, as important regulators of hepcidin expression in iron homeostasis. Therefore, we aimed to unravel why enhanced BMP expression in HCC patients does not lead to severe changes in iron metabolism. Initial analysis of the BMP4 and BMP6 expression patterns revealed enhanced expression on mRNA and protein level in HCC cell lines and tissue samples compared with primary human hepatocytes (PHHs) and normal liver tissues. However and interestingly, hepcidin expression was reduced in HCC cell lines and tissues. Analysis of BMP6 receptor expression revealed loss of BMP6-specific receptor subunit in HCC. To identify a possible regulatory mechanism causing lack of reaction to BMP4 we analyzed the expression of hemojuvelin (HJV), which is involved in iron metabolism as BMP co-receptor. HJV expression was markedly decreased in HCC cell lines and tissues. HJV promoter analysis revealed potential HNF-1 alpha and snail-binding sites, but functional analysis ruled out that these transcriptional regulators or promoter methylation are the cause of HJV downregulation in HCC. However, we identified AU-rich elements in the HJV 3'-untranslated region and revealed significantly faster decay of HJV mRNA in HCC cells as compared with PHH indicating decreased mRNA-stability as the reason for the loss of HJV expression in HCC. Laboratory Investigation (2011) 91, 1615-1623; doi: 10.1038/labinvest.2011.123; published online 22 August 2011