Maegdefrau, Ulrike and Arndt, Stephanie and Kivorski, Georgi and Hellerbrand, Claus and Bosserhoff, Anja-Katrin (2011) Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. LABORATORY INVESTIGATION, 91 (11). pp. 1615-1623. ISSN 0023-6837, 1530-0307
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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
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSCRIPTIONAL REPRESSOR SNAIL; TRANSFERRIN RECEPTOR 2; HEPCIDIN EXPRESSION; IN-VIVO; MALIGNANT-MELANOMA; HUMAN HEPATOCYTES; INTESTINAL-CELLS; GENE-EXPRESSION; LIVER; INTERLEUKIN-6; bone morphogenetic protein 4 and 6; hemojuvelin; hepatocellular carcinoma; hepcidin; iron metabolism |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 May 2020 08:37 |
| Last Modified: | 27 May 2020 08:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19892 |
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