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Journal of Cancer Research and Clinical Oncology

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01.10.2009 | Original Paper

Expression of hepcidin and other iron-regulatory genes in human hepatocellular carcinoma and its clinical implications

verfasst von: Hsi-Huang Tseng, Jan-Gowth Chang, Yaw-Huei Hwang, Kun-Tu Yeh, Yao-Li Chen, Hsin-Su Yu

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 10/2009

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Abstract

Purpose

We aimed to assess expression of ten iron-regulatory genes in hepatocellular carcinoma (HCC) and its clinical implications.

Methods

We used real-time polymerase chain reaction to measure ten iron-regulatory genes’ mRNA and Perls’ stain to assess iron stores in 50 HCCs and adjacent nontumor specimens. We compared the differences of gene expression and iron stores between tumor and nontumor specimens, and analyzed the relationships of gene expression with hepatic iron stores, patients’ hemoglobin levels and clinicopathologic parameters.

Results

Hepcidin, ceruloplasmin, transferrin, and transferrin receptor 2 were downregulated, while transferrin receptor 1 was upregulated in HCC. Hepcidin was markedly decreased in HCC but still correlated with hepatic iron stores. Iron-regulatory genes varied in their relationships of expression with clinicopathologic parameters.

Conclusions

Altered expression of iron-regulatory genes in HCC may disturb patient’s iron balance. Hepcidin may play a role in defending the body against HCC.

American Joint Committee on Cancer (1997) AJCC cancer staging manual. Lippincott-Raven, Philadelphia

Anderson GJ, Frazer DM (2005) Hepatic iron metabolism. Semin Liver Dis 25:420–432. doi:10.1055/s-2005-923314 CrossRefPubMed

Andrews NC (2004) Anemia of inflammation: the cytokine–hepcidin link. J Clin Invest 113:1251–1253PubMed

Andrews NC, Schmidt PJ (2007) Iron homeostasis. Annu Rev Physiol 69:69–85. doi:10.1146/annurev.physiol.69.031905.164337 CrossRefPubMed

Aoki CA, Rossaro L, Ramsamooj R, Brandhagen D, Burritt MF, Bowlus CL (2005) Liver hepcidin mRNA correlates with iron stores, but not inflammation, in patients with chronic hepatitis C. J Clin Gastroenterol 39:71–74PubMed

Bergmann OM, Mathahs MM, Broadhurst KA et al (2008) Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis? Lab Invest 88:1349–1357. doi:10.1038/labinvest.2008.95 CrossRefPubMed

Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF (2000) Molecular characterization of a case of atransferrinemia. Blood 96:4071–4074PubMed

Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DHG et al (2003) Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361:669–673. doi:10.1016/S0140-6736(03)12602-5 CrossRefPubMed

Bridle KR, Cheung TK, Murphy TL, Walters MM, Anderson GJ, Crawford DHG et al (2006) Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 30:106–112. doi:10.1111/j.1530-0277.2006.00002.x CrossRefPubMed

Courselaud B, Troadec M-B, Fruchon S, Ilyin G, Borot N, Leroyer P et al (2004) Strain and gender modulate hepatic hepcidin 1 and 2 mRNA expression in mice. Blood Cells Mol Dis 32:283–289. doi:10.1016/j.bcmd.2003.11.003 CrossRefPubMed

Detivaud L, Nemeth E, Boudjema K, Turlin B, Troadec MB, Leroyer P et al (2005) Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function. Blood 106:746–748. doi:10.1182/blood-2004-12-4855 CrossRefPubMed

Deugnier YM, Charalambous P, Lequilleuc D, Turlin B, Searle J, Brissot P et al (1993) Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients. Hepatology 18:1363–1369PubMed

Fujita N, Sugimoto R, Takeo M, Urawa N, Mifuji R, Tanaka H et al (2007) Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 13:97–104. doi:10.2119/2006-00057.Fujita CrossRefPubMed

Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD (1995) Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 92:2539–2543. doi:10.1073/pnas.92.7.2539 CrossRefPubMed

Hayashi A, Wada Y, Suzuki T, Shimizu A (1993) Studies on familial hypotransferrinemia: unique clinical course and molecular pathology. Am J Hum Genet 53:201–213PubMed

Hirohashi S, Ishak KG, Kojiro M, Wanless IR, Theise ND, Tsukuma H (2000) Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA et al (eds) World Health Organization classification of tumors, pathology and genetics of tumors of the digestive system. IARC Press, Lyon, pp 165–166

Holmstrom P, Gafvels M, Eriksson LC, Dzikaite V, Hultcrantz R, Eggertsen G et al (2006) Expression of iron regulatory genes in a rat model of hepatocellular carcinoma. Liver Int 26:976–985. doi:10.1111/j.1478-3231.2006.01316.x CrossRefPubMed

Kijima H, Sawada T, Tomosugi N, Kubota K (2008) Expression of hepcidin mRNA is uniformly suppressed in hepatocellular carcinoma. BMC Cancer 8:167. doi:10.1186/1471-2407-8-167 CrossRefPubMed

Kwok JC, Richardson DR (2002) The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit Rev Oncol Hematol 42:65–78. doi:10.1016/S1040-8428(01)00213-X CrossRefPubMed

Loreal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P et al (2002) Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol 36:851–856. doi:10.1016/S0168-8278(02)00042-9 CrossRefPubMed

Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM et al (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093. doi:10.1126/science.1104742 CrossRefPubMed

Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A et al (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98:8780–8785. doi:10.1073/pnas.151179498 CrossRefPubMed

Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I et al (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110:1037–1044PubMed

Ohtake T, Saito H, Hosoki Y, Inoue M, Miyoshi S, Suzuki Y et al (2007) Hepcidin is down-regulated in alcohol loading. Alcohol Clin Exp Res 31:2S–8S. doi:10.1111/j.1530-0277.2006.00279.x CrossRef

Pietrangelo A (2006) Hereditary hemochromatosis. Annu Rev Nutr 26:251–270. doi:10.1146/annurev.nutr.26.061505.111226 CrossRefPubMed

Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P et al (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276:7811–7819. doi:10.1074/jbc.M008923200 CrossRefPubMed

Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J et al (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33:21–22. doi:10.1038/ng1053 CrossRefPubMed

Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC (2007) Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 109:4038–4044. doi:10.1182/blood-2006-10-051755 CrossRefPubMed

Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3:1101–1108. doi:10.1038/nprot.2008.73 CrossRefPubMed

Searle J, Leggett BA, Crawford DHG, Powell LW (2002) Iron storage diseases. In: MacSween RNM, Burt AD, Portman BC, Ishak KG, Scheuer PJ, Anthony PP (eds) Pathology of the liver, 4th edn. Churchill Livingstone, London, pp 257–272

Tseng HH, Hwang YH, Yeh KT, Chang JG, Chen YL, Yu HS (2009) Reduced expression of C/EBPalpha protein in hepatocellular carcinoma is associated with advanced tumor stage and shortened patient survival. J Cancer Res Clin Oncol 135:241–247CrossRefPubMed

Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC (2002) Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 100:3776–3781. doi:10.1182/blood-2002-04-1260 CrossRefPubMed

Titel: Expression of hepcidin and other iron-regulatory genes in human hepatocellular carcinoma and its clinical implications
verfasst von: Hsi-Huang Tseng
Jan-Gowth Chang
Yaw-Huei Hwang
Kun-Tu Yeh
Yao-Li Chen
Hsin-Su Yu
Publikationsdatum: 01.10.2009
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 10/2009
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-009-0585-5

Springer Medizin

Expression of hepcidin and other iron-regulatory genes in human hepatocellular carcinoma and its clinical implications

Abstract

Purpose

Methods

Results

Conclusions

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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