Abstract
Recently, we revealed that bone morphogenetic protein (BMP) 4 is increased in hepatocellular carcinoma (HCC), and latest reports describe BMPs, in particular BMP6, as important regulators of hepcidin expression in iron homeostasis. The aim of this study was to unravel why enhanced BMP expression in HCC does not lead to severe changes in iron metabolism. Methods and Results: Initial analysis confirmed and newly revealed, respectively, enhanced mRNA and protein expression of both BMP4 and BMP6 in human HCC cell lines and tissues compared to primary human hepatocytes (PHH) and normal liver tissues. However and surprisingly, 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 the lack of response towards BMP4 we analyzed the expression of hemojuvelin (HJV), which is involved in iron metabolism acting as a BMP co-receptor. HJV expression was markedly decreased in HCC cell lines and tissues, and moreover, also in surrounding non-tumorous liver tissue. In line with this, we found reduced hepatic HJV expression in an experimental murine model bearing BMP expressing tumors. HJV promoter analysis revealed potential HNF-1α and snail binding sites, but functional analysis ruled out that these transcriptional regulators or promoter methylation are the cause of HJV down-regulation in HCC. However, we identified AU-rich elements in the HJV 3’-untranslated region. We revealed significantly faster decay of HJV mRNA in HCC cells as compared to PHH indicating decreased mRNA-stability as the reason for loss of HJV expression in HCC. Conclusion: Hepatic tumors decrease hemojuvelin expression, and herewith, inhibit inhibitory effects of BMPs on iron levels. Thus, regulation of iron homeostasis in HCC differs significantly from normal hepatic tissue.
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