Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-thalassaemia represents a group of diseases, in which ineffective erythropoiesis is accompanied by iron overload. In a mouse model of beta-thalassaemia, we observed that the liver expressed relatively low levels of hepcidin, which is a key factor in the regulation of iron absorption by the gut and of iron recycling by the reticuloendothelial system. It was hypothesised that, despite the overt iron overload, a putative plasma factor found in beta-thalassaemia might suppress liver hepcidin expression. Sera from beta-thalassaemia and haemochromatosis (C282Y mutation) patients were compared with those of healthy individuals regarding their capacity to induce changes the expression of key genes of iron metabolism in human HepG2 hepatoma cells. Sera from beta-thalassaemia major patients induced a major decrease in hepcidin (HAMP) and lipocalin2 (oncogene 24p3) (LCN2) expression, as well as a moderate decrease in haemojuvelin (HFE2) expression, compared with sera from healthy individuals. A significant correlation was found between the degree of downregulation of HAMP and HFE2 induced by beta-thalassaemia major sera (r = 0.852, P < 0.0009). Decreased HAMP expression was also found in HepG2 cells treated with sera from beta-thalassaemia intermedia patients. In contrast, the majority of sera from hereditary haemochromatosis patients induced an increase in HAMP expression, which correlated with transferrin (Tf) saturation (r = 0.765, P < 0.0099). Our results suggest that, in beta-thalassaemia, serum factors might override the potential effect of iron overload on HAMP expression, thereby providing an explanation for the failure to arrest excessive intestinal iron absorption in these patients.
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PMID:Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. 1693 99

Hemojuvelin (HJV), encoded by the gene HFE2, is a critical upstream regulator of hepcidin expression. Hepcidin, the central iron regulatory hormone, is secreted from hepatocytes, whereas HFE2 is highly expressed in skeletal muscle and liver. Previous studies demonstrated that HJV is a GPI-anchored protein, binds the proteins neogenin and bone morphogenetic proteins (BMP2 and BMP4), and can be released from the cell membrane (shedding). In this study, we investigated the physiological significance and the underlying mechanism of HJV shedding. In acutely iron-deficient rats with markedly suppressed hepatic hepcidin expression, we detected an early phase increase of serum HJV with no significant change of either HFE2 mRNA or protein levels in gastrocnemius muscle. Studies in both C2C12 (a mouse myoblast cell line) and HepG2 (a human hepatoma cell line) cells showed active HJV shedding, implying that both skeletal muscle and liver could be the source of serum HJV. In agreement with the observations in iron-deficient rats, HJV shedding in these cell lines was down-regulated by holo-transferrin in a concentration-dependent manner. Our present study showing that knock-down of endogenous neogenin, a HJV receptor, in C2C12 cells suppresses HJV shedding and that overexpression of neogenin in HEK293 cells markedly enhances this process, suggests that membrane HJV shedding is mediated by neogenin. The finding that neither BMP4 nor its antagonist, noggin, was able to alter HJV shedding support the lack of involvement of BMP signaling pathway in this process.
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PMID:Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. 1733 53

HFE2 (hemochromatosis type 2 gene) is highly expressed in skeletal muscle and liver hepatocytes. Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and enhances the BMP-induced hepcidin expression. Hepcidin is a central iron regulatory hormone predominantly secreted from hepatocytes. HJV also binds neogenin, a membrane protein widely expressed in many tissues. Neogenin is required for the processing and release of HJV from cells. The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a human hepatoma cell line. Knockdown of endogenous neogenin markedly suppresses HJV release but has no evident effect on HJV trafficking to the plasma membrane. The addition of a soluble neogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the cell surface. At the plasma membrane it undergoes endocytosis in a dynamin-independent but cholesterol-dependent manner. The additional findings that HJV release is coupled to lysosomal degradation of neogenin and that cholesterol depletion by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface.
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PMID:Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. 1844 98

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Iron overload represents a significant risk factor in the development of HCC. Hereditary hemochromatosis (HH) is a genetic iron overload disease characterized by hepatic iron accumulation. The potential link between these two conditions leads to significant curiosity about regulation of iron homeostasis. Importantly, one of the HH genes, HAMP, encodes the master regulator of iron homeostasis, hepcidin, which is expressed by hepatocytes. Recent studies have shown that the remaining HH genes are either upstream regulators (HFE, HFE2 and TFR2) or downstream targets (FPN) of hepcidin. Moreover, the presence of additional signaling pathways in the liver that contribute to regulation of hepcidin expression has been documented. The function of these iron-regulatory proteins is currently being investigated to determine if they play a role in abnormal iron uptake in tumors. This review summarizes these recent studies and briefly discusses new directions in the treatment of iron overload in HCC patients.
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PMID:Abnormal iron uptake and liver cancer. 1957 63