Modulation of Iron-Regulatory Genes in Human Hepatocellular Carcinoma and Its Physiological Consequences

Tan, Michelle; Kumarasinghe, Marian Priyanthi; Wang, Suk Mei; Ooi, London Lucien; Aw, Swee Eng; Hui, Kam M.

doi:10.3181/0807-rm-227

Cited by 48 publications

(50 citation statements)

References 33 publications

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“…patients (6) . The present study showed an increase in the serum levels or positive correlation with CTP or BCLC in transferrin (in CI group), iron (in CI and HCC group) and ferritin saturation (in HCC group), which is in accordance with the literature (11,28,30,38) . A possible explanation is the fact that the iron absorbance through transferrin receptors is higher in hepatocellular carcinoma than in a normal liver, making the transferrin a marker of the presence of HCC (28) .…”

Section: Discussionsupporting

confidence: 80%

“…Some (11,28,30,38) affirm that there are increases in serum transferrin, iron and ferritin saturation levels, positively correlated with the presence of HCV, cirrhosis and HCC, especially in more advanced stages of the diseases. However, other authors have not observed alterations in the iron levels (4) or report reduction in liver cirrhosis and HCC Port GZ, Oliveira K, Soldera J, Tovo CV.…”

Section: Discussionmentioning

confidence: 99%

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Biochemical Nutritional Profile of Liver Cirrhosis Patients With Hepatocellular Carcinoma

Port

Oliveira

Soldera

et al. 2014

Arq. Gastroenterol.

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-Context -Liver cirrhosis patients with hepatocellular carcinoma present nutritional alterations and metabolic disorders that negatively impact the prognosis. Objective -The objective is to identify alterations in the metabolism of macro and micronutrients among liver cirrhosis patients with and without hepatocellular carcinoma and their relation to the Child-Turcote-Pugh score and Barcelona Clinic Liver Cancer staging. Methods -Analytical transversal study, with 31 hepatocellular carcinoma patients and 48 liver cirrhosis patients. Laboratorial exams were carried out. The existence of an association between the biochemical parameters and the disease severity as well as the presence of hepatocellular carcinoma was assessed. Results -The metabolic-nutritional profile of liver cirrhosis patients caused by the hepatitis C virus and hepatocellular carcinoma showed alterations, specifically the lipid (total cholesterol, HDL and triglycerides), protein (albumin, creatinine and uric acid), iron (transferrin, iron and ferritin saturation), hematocrit and hemoglobin, zinc and B12 vitamin profiles. There is a relation between nutritional biochemical markers and the Child-Turcote-Pugh, as well as Barcelona Clinic Liver Cancer staging. Conclusion -Considering the existence of alterations in the metabolism of nutrients in liver cirrhosis patients with and without hepatocellular carcinoma, and also that conventional nutritional assessment methods present limitations for this population, the biochemical laboratorial exams are valid to complement the diagnosis of the nutritional state in a quick and practical manner.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Biochemical Nutritional Profile of Liver Cirrhosis Patients With Hepatocellular Carcinoma

Port

Oliveira

Soldera

et al. 2014

Arq. Gastroenterol.

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“…Thus, it has been described that hepcidin mRNA expression is uniformly suppressed in HCC, whereas serum concentration of hepcidin was not correlated with mRNA expression in these studies. [30][31][32] However, up to now the influence of enhanced BMP levels of hepcidin expression in HCC was not analyzed. Remarkably, in spite of enhanced BMP expression in HCC, we were able to detect reduced hepcidin mRNA and protein expression levels in HCC tissues and cells.…”

Section: Discussionmentioning

confidence: 99%

“…Actually, two prior studies reported no significant difference in hepcidin or HJV expression, respectively, between HCC and surrounding non-tumorous livers. 31,32 It has to be noted that both studies had been performed with tissue specimens from patients with different ethnic background than in our study. Still, it also has to be considered that some of the mechanisms, which we identified in this study as potential explanation for the missing effect of enhanced BMP levels on hepatic hepcidin expression are already affected in pre-malignant diseased liver tissue, and herewith, may affect iron homeostasis in patients with chronic liver disease.…”

Section: Loss Of Hjv In Hccmentioning

confidence: 92%

Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma

Maegdefrau

Arndt

Kivorski

et al. 2011

Laboratory Investigation

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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-1a 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 0 -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. In the last few years, our knowledge of the regulation of iron homeostasis significantly increased.1 Thus, bone morphogenetic proteins (BMPs) have been newly identified as regulators of hepatic hepcidin expression.2-5 HJV (hemojuvelin), a member of the repulsive guidance molecule family (RGM family), acts as a BMP co-receptor and triggers the binding of BMP ligands to BMP receptors to enhance hepcidin expression.3,4 For a long time BMP2, 4, 6 and 9 were postulated as important regulators of hepcidin expression in vitro, 6,7 whereas in latest publications along with others, we described especially BMP6 as key endogenous regulator of hepcidin expression and iron metabolism in vivo. 6,[8][9][10] It is furthermore known that BMPs not only have an important role in the iron sensing pathway but are also involved in the development and progression of different kinds of cancer. [11][12][13] We recently demonstrated that BMP4 promotes the progression of hepatocellular carcinoma (HCC).14 Noteworthy, up to now the impact of enhanced BMP expression on (changes in) iron metabolism in HCC, one of the most common cancers worldwide, 15 has not been addressed. Thus, one may hypothesize that patients with enhanced BMP expression levels develop anemia through increased levels of hepcidin, which is responsible for internalization and degradation of ferroportin to limit intestinal iron uptake. 16,17 However, along with others, we found increased iron levels in the serum of HCC patients. 18,19Therefore, we aimed to unravel the reason why HCC patients with enhanced BMP exp...

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“…It has been well documented that iron homeostasis and iron regulatory pathways are abnormal in human HCC (30)(31)(32). Thus, it is likely that iron chelators targeting excess iron may suppress HCC and bring clinical benefits to HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Iron Deprivation Suppresses Hepatocellular Carcinoma Growth in Experimental Studies

Hao

Huang

et al. 2011

Clinical Cancer Research

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Purpose: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and iron overload is a significant risk factor in the development of HCC. In this study, we investigated the potential application of depriving iron by a novel iron chelator, thiosemicarbazone-24 (TSC24), in HCC treatment.Experimental Design: Two HCC cell lines and HFE knockout (HFE À/À ) mice were used to determine iron chelation efficiency of TSC24. The anticancer effects of TSC24 on HCC were analyzed in vitro and in athymic xenograft mouse models.Results: Treatment with TSC24 significantly decreased the cellular iron concentration in hepatoma cells and the serum iron concentration in HFE À/À mice by blocking iron uptake and interfering with normal regulation of iron levels. Moreover, the viability of HCC cell lines was reduced by TSC24. Confirming the mechanism of the agent, this decrease in viability could be partially rescued by addition of exogenous iron. TSC24 also suppressed tumor growth in athymic mice bearing human HCC xenografts in a concentration-dependent manner, without apparent toxicity in parallel with a decrease in the serum iron level. Further studies revealed that TSC24 efficiently triggered cell-cycle arrest and apoptosis in Hep3B and HepG2 cell lines. Conclusions: TSC24 is a potent iron chelator that suppresses human HCC tumor growth by disrupting iron homeostasis, reducing available iron, and triggering cell-cycle arrest and apoptosis, without apparent host toxicity at effective doses. Thus, TSC24 shows great potential for the treatment of HCC. Clin Cancer Res; 17(24); 7625-33. Ó2011 AACR.

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Modulation of Iron-Regulatory Genes in Human Hepatocellular Carcinoma and Its Physiological Consequences

Cited by 48 publications

References 33 publications

Biochemical Nutritional Profile of Liver Cirrhosis Patients With Hepatocellular Carcinoma

Biochemical Nutritional Profile of Liver Cirrhosis Patients With Hepatocellular Carcinoma

Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma

Iron Deprivation Suppresses Hepatocellular Carcinoma Growth in Experimental Studies

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