Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities

doi:10.1007/s13238-014-0119-z

Protein Cell

2015, Vol. 6

Issue (2) : 88-100 https://doi.org/10.1007/s13238-014-0119-z

REVIEW

Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities

Caiguo Zhang^1,^*(

),Fan Zhang²

1. Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA
2. Orthopedics Department, Changhai Hospital Affiliated to Second Military Medical University, Shanghai 200433, China

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Abstract

Excess iron is tightly associated with tumorigenesis in multiple human cancer types through a variety of mechanisms including catalyzing the formation of mutagenic hydroxyl radicals, regulating DNA replication, repair and cell cycle progression, affecting signal transduction in cancer cells, and acting as an essential nutrient for proliferating tumor cells. Thus, multiple therapeutic strategies based on iron deprivation have been developed in cancer therapy. During the past few years, our understanding of genetic association and molecular mechanisms between iron and tumorigenesis has expanded enormously. In this review, we briefly summarize iron homeostasis in mammals, and discuss recent progresses in understanding the aberrant iron metabolism in numerous cancer types, with a focus on studies revealing altered signal transduction in cancer cells.

Keywords Iron tumorigenesis p53 Wnt DNA repair cell cycle

Corresponding Author(s): Caiguo Zhang

Issue Date: 05 February 2015

Cite this article:

Caiguo Zhang,Fan Zhang. Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities[J]. Protein Cell, 2015, 6(2): 88-100.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-014-0119-z
https://academic.hep.com.cn/pac/EN/Y2015/V6/I2/88

1	Chaston TB, Richardson DR (2003) Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity. Am J Hematol 73: 200-210 https://doi.org/10.1002/ajh.10348
2	Chen G, Fillebeen C, Wang J, Pantopoulos K (2007) Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis 28: 785-791 https://doi.org/10.1093/carcin/bgl210
3	Chen Y, Zhang Z, Yang K, Du J, Xu Y, Liu S (2014) Myeloid zincfinger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress. Oncogene https://doi.org/10.1038/onc.2014.310
4	Cheng Z, Dai LL, Song YN, Kang Y, Si JM, Xia J, Liu YF (2014) Regulatory effect of iron regulatory protein-2 on iron metabolism in lung cancer. Genet Mol Res 13: 5514-5522 https://doi.org/10.4238/2014.July.25.5
5	Cho H, Kim JH (2009) Lipocalin2 expressions correlate significantly with tumor differentiation in epithelial ovarian cancer. J Histochem Cytochem 57: 513-521 https://doi.org/10.1369/jhc.2009.953257
6	Choi AM, Alam J (1996) Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidantinduced lung injury. Am J Respir Cell Mol Biol 15: 9-19 https://doi.org/10.1165/ajrcmb.15.1.8679227
7	Crepin R, Goenaga AL, Jullienne B, Bougherara H, Legay C, Benihoud K, Marks JD, Poul MA (2010) Development of human single-chain antibodies to the transferrin receptor that effectively antagonize the growth of leukemias and lymphomas. Cancer Res 70: 5497-5506 https://doi.org/10.1158/0008-5472.CAN-10-0938
8	Daniels TR, Bernabeu E, Rodriguez JA, Patel S, Kozman M, Chiappetta DA, Holler E, Ljubimova JY, Helguera G, Penichet ML (2012) The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta 1820: 291-317 https://doi.org/10.1016/j.bbagen.2011.07.016
9	Dayani PN, Bishop MC, Black K, Zeltzer PM (2004) Desferoxamine (DFO)-mediated iron chelation: rationale for a novel approach to therapy for brain cancer. J Neurooncol 67: 367-377 https://doi.org/10.1023/B:NEON.0000024238.21349.37
10	Denic S, Agarwal MM (2007) Nutritional iron deficiency: an evolutionary perspective. Nutrition 23: 603-614 https://doi.org/10.1016/j.nut.2007.05.002
11	Dongiovanni P, Fracanzani AL, Cairo G, Megazzini CP, Gatti S, Rametta R, Fargion S, Valenti L (2010) Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. Am J Pathol 176: 1006-1017 https://doi.org/10.2353/ajpath.2010.090249
12	Duarte DC, Nicolau A, Teixeira JA, Rodrigues LR (2011) The effect of bovine milk lactoferrin on human breast cancer cell lines. J Dairy Sci 94: 66-76 https://doi.org/10.3168/jds.2010-3629
13	Dunn LL, Suryo Rahmanto Y, Richardson DR (2007) Iron uptake and metabolism in the new millennium. Trends Cell Biol 17: 93-100 https://doi.org/10.1016/j.tcb.2006.12.003
14	Eberhard Y, McDermott SP, Wang X, Gronda M, Venugopal A, Wood TE, Hurren R, Datti A, Batey RA, Wrana J (2009) Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood 114: 3064-3073 https://doi.org/10.1182/blood-2009-03-209965
15	Emanuele D, Tuason I, Edwards QT (2014) HFE-associated hereditary hemochromatosis: overview of genetics and clinical implications for nurse practitioners in primary care settings. J Am Assoc Nurse Pract 26: 113-122
16	Enyedy EA, Primik MF, Kowol CR, Arion VB, Kiss T, Keppler BK (2011) Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study. Dalton Trans 40: 5895-5905 https://doi.org/10.1039/c0dt01835j
17	Fernandez CA, Yan L, Louis G, Yang J, Kutok JL, Moses MA (2005) The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res 11: 5390-5395 https://doi.org/10.1158/1078-0432.CCR-04-2391
18	Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16: 4604-4613
19	Fu D, Richardson DR (2007) Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion. Blood 110: 752-761 https://doi.org/10.1182/blood-2007-03-076737
20	Gkouvatsos K, Papanikolaou G, Pantopoulos K (2012) Regulation of iron transport and the role of transferrin. Biochim Biophys Acta 1820: 188-202 https://doi.org/10.1016/j.bbagen.2011.10.013
21	Hamalainen P, Saltevo J, Kautiainen H, Mantyselka P, Vanhala M (2012) Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study. Cardiovasc Diabetol 11: 116 https://doi.org/10.1186/1475-2840-11-116
22	Hewitson KS, McNeill LA, Elkins JM, Schofield CJ (2003) The role of iron and 2-oxoglutarate oxygenases in signalling. Biochem Soc Trans 31: 510-515 https://doi.org/10.1042/BST0310510
23	Hohaus S, Massini G, Giachelia M, Vannata B, Bozzoli V, Cuccaro A, D’Alo F, Larocca LM, Raymakers RA, Swinkels DW (2010) Anemia in Hodgkin’s lymphoma: the role of interleukin-6 and hepcidin. J Clin Oncol 28: 2538-2543 https://doi.org/10.1200/JCO.2009.27.6873
24	Hong CC, Ambrosone CB, Ahn J, Choi JY, McCullough ML, Stevens VL, Rodriguez C, Thun MJ, Calle EE (2007) Genetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomark Prev 16: 1784-1794 https://doi.org/10.1158/1055-9965.EPI-07-0247
25	Hou Y, Zhang S, Wang L, Li J, Qu G, He J, Rong H, Ji H, Liu S (2012) Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Gene 511: 398-403 https://doi.org/10.1016/j.gene.2012.09.060
26	Iwasaki K, Ray PD, Huang BW, Sakamoto K, Kobayashi T, Tsuji Y (2013) Role of AMP-activated protein kinase in ferritin H gene expression by resveratrol in human T cells. Biochemistry 52: 5075-5083 https://doi.org/10.1021/bi400399f
27	Jakszyn PG, Allen NE, Lujan-Barroso L, Gonzalez CA, Key TJ, Fonseca-Nunes A, Tjonneland A, Fons-Johnsen N, Overvad K, Teucher B (2012) Nitrosamines and heme iron and risk of prostate cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomark Prev 21: 547-551 https://doi.org/10.1158/1055-9965.EPI-11-1181
28	Jiang XP, Elliott RL, Head JF (2010) Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res 30: 759-765
29	Josson S, Matsuoka Y, Gururajan M, Nomura T, Huang WC, Yang X, Lin JT, Bridgman R, Chu CY, Johnstone PA (2013) Inhibition of beta2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells. PLoS One 8: e68366 https://doi.org/10.1371/journal.pone.0068366
30	Kalousova M, Krechler T, Jachymova M, Kubena AA, Zak A, Zima T (2012) Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study. Tumour Biol 33: 1695-1700 https://doi.org/10.1007/s13277-012-0426-z
31	Kaplan CD, Kaplan J (2009) Iron acquisition and transcriptional regulation. Chem Rev 109: 4536-4552 https://doi.org/10.1021/cr9001676
32	Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12: 9-22
33	Koc M, Taysi S, Sezen O, Bakan N (2003) Levels of some acutephase proteins in the serum of patients with cancer during radiotherapy. Biol Pharm Bull 26: 1494-1497 https://doi.org/10.1248/bpb.26.1494
34	Koreth J, Antin JH (2010) Iron overload in hematologic malignancies and outcome of allogeneic hematopoietic stem cell transplantation. Haematologica 95: 364-366 https://doi.org/10.3324/haematol.2009.017244
35	Kowdley KV (2004) Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127: S79-86 https://doi.org/10.1016/j.gastro.2004.09.019
36	Kukulj S, Jaganjac M, Boranic M, Krizanac S, Santic Z, Poljak-Blazi M (2010) Altered iron metabolism, inflammation, transferrin receptors, and ferritin expression in non-small-cell lung cancer. Med Oncol 27: 268-277 https://doi.org/10.1007/s12032-009-9203-2
37	Kumar D, Viberg J, Nilsson AK, Chabes A (2010) Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res 38: 3975-3983 https://doi.org/10.1093/nar/gkq128
38	Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, Choi AM (1997) Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem 272: 5375-5381 https://doi.org/10.1074/jbc.272.9.5375
39	Lee SH, Pyo CW, Hahm DH, Kim J, Choi SY (2009) Iron-saturated lactoferrin stimulates cell cycle progression through PI3K/Akt pathway. Mol Cells 28: 37-42 https://doi.org/10.1007/s10059-009-0102-3
40	Leng X, Ding T, Lin H, Wang Y, Hu L, Hu J, Feig B, Zhang W, Pusztai L, Symmans WF (2009) Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer Res 69: 8579-8584 https://doi.org/10.1158/0008-5472.CAN-09-1934
41	Leng X, Wu Y, Arlinghaus RB (2011) Relationships of lipocalin 2 with breast tumorigenesis and metastasis. J Cell Physiol 226: 309-314 https://doi.org/10.1002/jcp.22403
42	Leung L, Radulovich N, Zhu CQ, Organ S, Bandarchi B, Pintilie M, To C, Panchal D, Tsao MS (2012) Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma. PLoS One 7: e46677 https://doi.org/10.1371/journal.pone.0046677
43	Lill R, Hoffmann B, Molik S, Pierik AJ, Rietzschel N, Stehling O, Uzarska MA, Webert H, Wilbrecht C, Muhlenhoff U (2012) The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism. Biochim Biophys Acta 1823: 1491-1508 https://doi.org/10.1016/j.bbamcr.2012.05.009
44	Lin X, Yang H, Zhou L, Guo Z (2011) Nrf2-dependent induction of NQO1 in mouse aortic endothelial cells overexpressing catalase. Free Radic Biol Med 51: 97-106 https://doi.org/10.1016/j.freeradbiomed.2011.04.020
45	Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274: 24147-24152 https://doi.org/10.1074/jbc.274.34.24147
46	Lovejoy DB, Richardson DR (2003) Iron chelators as anti-neoplastic agents: current developments and promise of the PIH class of chelators. Curr Med Chem 10: 1035-1049 https://doi.org/10.2174/0929867033457557
47	MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17: 9-26 https://doi.org/10.1016/j.devcel.2009.06.016
48	MacKenzie EL, Iwasaki K, Tsuji Y (2008) Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal 10: 997-1030 https://doi.org/10.1089/ars.2007.1893
49	Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, Callander N, Katodritou E, Tussing-Humphreys L, Rivera S (2010) In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 116: 3635-3644 https://doi.org/10.1182/blood-2010-03-274571
50	Mannelqvist M, Stefansson IM, Wik E, Kusonmano K, Raeder MB, Oyan AM, Kalland KH, Moses MA, Salvesen HB, Akslen LA (2012) Lipocalin 2 expression is associated with aggressive features of endometrial cancer. BMC Cancer 12: 169 https://doi.org/10.1186/1471-2407-12-169
51	Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454: 436-444 https://doi.org/10.1038/nature07205
52	Martin JH, Alalami O, Yaqoob F (2000) Differential effects of retinoids on nitric oxide production by promonocytic U937 cells and ZR-75-1 human breast cancer cells. Oncol Rep 7: 219-223
53	Miller JL (2013) Iron deficiency anemia: a common and curable disease. Cold Spring Harb Perspect Med 3: a011866 https://doi.org/10.1101/cshperspect.a011866
54	Miyabe I, Kunkel TA, Carr AM (2011) The major roles of DNA polymerases epsilon and delta at the eukaryotic replication fork are evolutionarily conserved. PLoS Genet 7: e1002407 https://doi.org/10.1371/journal.pgen.1002407
55	Molina-Montes E, Wark PA, Sanchez MJ, Norat T, Jakszyn P, LujanBarroso L, Michaud DS, Crowe F, Allen N, Khaw KT (2012) Dietary intake of iron, heme-iron and magnesium and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort. Int J Cancer 131: E1134-1147 https://doi.org/10.1002/ijc.27547
56	Moser JC, Rawal M, Wagner BA, Du J, Cullen JJ, Buettner GR (2013) Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer. Redox Biol 2: 22-27 https://doi.org/10.1016/j.redox.2013.11.005
57	Muckenthaler MU, Galy B, Hentze MW (2008) Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 28: 197-213 https://doi.org/10.1146/annurev.nutr.28.061807.155521
58	Mukhopadhyay CK, Mazumder B, Fox PL (2000) Role of hypoxiainducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 275: 21048-21054 https://doi.org/10.1074/jbc.M000636200
59	Munoz M, Gomez-Ramirez S, Martin-Montanez E, Auerbach M (2014) Perioperative anemia management in colorectal cancer patients: a pragmatic approach. World J Gastroenterol 20: 1972-1985 https://doi.org/10.3748/wjg.v20.i8.1972
60	Oh WK (2002) The evolving role of estrogen therapy in prostate cancer. Clin Prostate Cancer 1: 81 -89 https://doi.org/10.3816/CGC.2002.n.009
61	Ornstein DL, Zacharski LR (2007) Iron stimulates urokinase plasminogen activator expression and activates NF-kappa B in human prostate cancer cells. Nutr Cancer 58: 115-126 https://doi.org/10.1080/01635580701308265
62	Orrenius S, Nicotera P, Zhivotovsky B (2011) Cell death mechanisms and their implications in toxicology. Toxicol Sci 119: 3-19 https://doi.org/10.1093/toxsci/kfq268
63	Osborne NJ, Gurrin LC, Allen KJ, Constantine CC, Delatycki MB, McLaren CE, Gertig DM, Anderson GJ, Southey MC, Olynyk JK (2010) HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology 51: 1311 -1318 https://doi.org/10.1002/hep.23448
64	Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L (2012) Mechanisms of mammalian iron homeostasis. Biochemistry 51: 5705-5724 https://doi.org/10.1021/bi300752r
65	Park KS, Kim H, Kim NG, Cho SY, Choi KH, Seong JK, Paik YK (2002) Proteomic analysis and molecular characterization of tissue ferritin light chain in hepatocellular carcinoma. Hepatology 35: 1459-1466 https://doi.org/10.1053/jhep.2002.33204
66	Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS (2007) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117: 1926-1932 https://doi.org/10.1172/JCI31370
67	Preston BD, Albertson TM, Herr AJ (2010) DNA replication fidelity and cancer. Semin Cancer Biol 20: 281 -293 https://doi.org/10.1016/j.semcancer.2010.10.009
68	Pusatcioglu CK, Nemeth E, Fantuzzi G, Llor X, Freels S, TussingHumphreys L, Cabay RJ, Linzmeier R, Ng D, Clark J (2014) Systemic and tumor level iron regulation in men with colorectal cancer: a case control study. Nutr Metab (Lond)11: 21 https://doi.org/10.1186/1743-7075-11-21
69	Radulescu S, Brookes MJ, Salgueiro P, Ridgway RA, McGhee E, Anderson K, Ford SJ, Stones DH, Iqbal TH, Tselepis C (2012) Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo. Cell Rep 2: 270-282 https://doi.org/10.1016/j.celrep.2012.07.003
70	Richardson DR, Kalinowski DS, Richardson V, Sharpe PC, Lovejoy DB, Islam M, Bernhardt PV (2009) 2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: redox activity, iron complexation and characterization of their antitumor activity. J Med Chem 52: 1459-1470 https://doi.org/10.1021/jm801585u
71	Romero A, Ramos E, de Los Rios C, Egea J, Del Pino J, Reiter RJ (2014) A review of metal-catalyzed molecular damage: protection by melatonin. J Pineal Res 56: 343-370 https://doi.org/10.1111/jpi.12132
72	Rossi E (2005) Hepcidin – the iron regulatory hormone. Clin Biochem Rev 26: 47-49
73	Rouault TA (2003) How mammals acquire and distribute iron needed for oxygen-based metabolism. PLoS Biol 1: E79 https://doi.org/10.1371/journal.pbio.0000079
74	Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2: 406-414 https://doi.org/10.1038/nchembio807
75	Sakurai K, Sohda T, Ueda S, Tanaka T, Hirano G, Yokoyama K, Mori hara D, Aanan A, Takeyama Y, Irie M (2014) Immunohistochemi cal demonstration of transferri n receptor 1 and 2 in human hepatocellular carcinoma tissue. Hepatogastroenterology 61: 426-430
76	Sarkar A, Sil PC (2014) Iron oxide nanoparticles mediated cytotoxicity via PI3K/AKT pathway: role of quercetin. Food Chem Toxicol 71: 106-115 https://doi.org/10.1016/j.fct.2014.06.003
77	Shen J, Sheng X, Chang Z, Wu Q, Wang S, Xuan Z, Li D, Wu Y, Shang Y, Kong X (2014) Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell Rep 7: 180-193 https://doi.org/10.1016/j.celrep.2014.02.042
78	Shiiba M, Saito K, Fushimi K, Ishigami T, Shinozuka K, Nakashima D, Kouzu Y, Koike H, Kasamatsu A, Sakamoto Y (2013) Lipocalin-2 is associated with radioresistance in oral cancer and lung cancer cells. Int J Oncol 42: 1197-1204
79	Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Chekhun VF, Beland FA, Pogribny IP (2011) Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat 126: 63-71 https://doi.org/10.1007/s10549-010-0849-4
80	Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 267: 204-215 https://doi.org/10.1016/j.canlet.2008.03.028
81	Siriwardana G, Seligman PA (2013) Two cell cycle blocks caused by iron chelation of neuroblastoma cells: separating cell cycle events associated with each block. Physiol Rep 1: e00176 https://doi.org/10.1002/phy2.176
82	Song S, Christova T, Perusini S, Alizadeh S, Bao RY, Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M (2011) Wnt inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Res 71: 7628-7639 https://doi.org/10.1158/0008-5472.CAN-11-2745
83	Stocker R (1990) Induction of haem oxygenase as a defence against oxidative stress. Free Radic Res Commun 9: 101 -112 https://doi.org/10.3109/10715769009148577
84	Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G (1999) Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem 274: 24142-24146 https://doi.org/10.1074/jbc.274.34.24142
85	Tammariello AE, Milner JA (2010) Mouse models for unraveling the importance of diet in colon cancer prevention. J Nutr Biochem 21: 77-88 https://doi.org/10.1016/j.jnutbio.2009.09.014
86	Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM (2009) Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences. Exp Biol Med (Maywood)234: 693-702 https://doi.org/10.3181/0807-RM-227
87	Tenga MJ, Lazar IM (2014) Proteomic study reveals a functional network of cancer markers in the G1-Stage of the breast cancer cell cycle. BMC Cancer 14: 710 https://doi.org/10.1186/1471-2407-14-710
88	Thomas C, Mackey MM, Diaz AA, Cox DP (2009) Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep 14: 102-108 https://doi.org/10.1179/135100009X392566
89	Torti SV, Torti FM (2013) Iron and cancer: more ore to be mined. Nat Rev Cancer 13: 342-355 https://doi.org/10.1038/nrc3495
90	Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal 10: 1343-1374 https://doi.org/10.1089/ars.2007.1957
91	Tsui KH, Chung LC, Wang SW, Feng TH, Chang PL, Juang HH (2013) Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells. J Mol Endocrinol 51: 131 -141 https://doi.org/10.1530/JME-13-0090
92	Vakkala M, Paakko P, Soini Y (2000) eNOS expression is associated with the estrogen and progesterone receptor status in invasive breast carcinoma. Int J Oncol 17: 667-671
93	Valerio LG (2007) Mammalian iron metabolism. Toxicol Mech. Methods 17: 497-517 https://doi.org/10.1080/15376510701556690
94	Vescio RA, Connors KM, Bordin GM, Robb JA, Youngkin T, Umbreit JN, Hoffman RM (1990) The distinction of small cell and nonsmall cell lung cancer by growth in native-state histoculture. Cancer Res 50: 6095-6099
95	von Maltzahn J, Chang NC, Bentzinger CF, Rudnicki MA (2012) Wnt signaling in myogenesis. Trends Cell Biol 22: 602-609 https://doi.org/10.1016/j.tcb.2012.07.008
96	Wang J, Pantopoulos K (2002) Conditional derepression of ferritin synthesis in cells expressing a constitutive IRP1 mutant. Mol Cell Biol 22: 4638-4651 https://doi.org/10.1128/MCB.22.13.4638-4651.2002
97	Wang J, Li Q, Ou Y, Han Z, Li K, Wang P, Zhou S (2011) Inhibition of tumor growth by recombinant adenovirus containing human lactoferrin through inducing tumor cell apoptosis in mice bearing EMT6 breast cancer. Arch Pharm Res 34: 987-995 https://doi.org/10.1007/s12272-011-0616-z
98	Wang N, Wei H, Yin D, Lu Y, Zhang Y, Jiang D, Jiang Y, Zhang S (2014) Cyclin D1b overexpression inhibits cell proliferation and induces cell apoptosis in cervical cancer cells in vitro and in vivo. Int J Clin Exp Pathol 7: 4016-4023
99	Ward PP, Mendoza-Meneses M, Cunningham GA, Conneely OM (2003) Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol 23: 178-185 https://doi.org/10.1128/MCB.23.1.178-185.2003
100	Wu Y, Brosh RM Jr (2012) DNA helicase and helicase-nuclease enzymes with a conserved iron-sulfur cluster. Nucleic Acids Res 40: 4247-4260 https://doi.org/10.1093/nar/gks039
101	Wyllie S, Liehr JG (1997) Release of iron from ferritin storage by redox cycling of stilbene and steroid estrogen metabolites: a mechanism of induction of free radical damage by estrogen. Arch Biochem Biophys 346: 180-186 https://doi.org/10.1006/abbi.1997.0306
102	Xiong W, Wang L, Yu F (2014) Regulation of cellular iron metabolism and its implications in lung cancer progression. Med Oncol 31: 28 https://doi.org/10.1007/s12032-014-0028-2
103	Xue X, Shah YM (2013) Intestinal iron homeostasis and colon tumorigenesis. Nutrients 5: 2333-2351 https://doi.org/10.3390/nu5072333
104	Xue X, Taylor M, Anderson E, Hao C, Qu A, Greenson JK, Zimmermann EM, Gonzalez FJ, Shah YM (2012) Hypoxiainducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res 72: 2285-2293 https://doi.org/10.1158/0008-5472.CAN-11-3836
105	Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, Strong RK, Zurakowski D, Moses MA (2009) Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A 106: 3913-3918 https://doi.org/10.1073/pnas.0810617106
106	Yang J, McNeish B, Butterfield C, Moses MA (2013) Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB J 27: 45-50 https://doi.org/10.1096/fj.12-211730
107	Yildirim A, Meral M, Kaynar H, Polat H, Ucar EY (2007) Relationship between serum levels of some acute-phase proteins and stage of disease and performance status in patients with lung cancer. Med Sci Monit 13: CR195-200
108	Yu Y, Wong J, Lovejoy DB, Kalinowski DS, Richardson DR (2006) Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res 12: 6876-6883 https://doi.org/10.1158/1078-0432.CCR-06-1954
109	Zhang C (2014) Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control. Protein Cell 5: 750-760 https://doi.org/10.1007/s13238-014-0083-7
110	Zhang F, Wang W, Tsuji Y, Torti SV, Torti FM (2008) Posttranscriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem 283: 33911-33918 https://doi.org/10.1074/jbc.M806432200
111	Zhang F, Tao Y, Zhang Z, Guo X, An P, Shen Y, Wu Q, Yu Y, Wang F (2012) Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica 97: 1826-1835 https://doi.org/10.3324/haematol.2012.063974
112	Zhang C, Liu G, Huang M (2014) Ribonucleotide reductase metallocofactor: assembly, maintenance and inhibition. Front Biol (Beijing)9: 104-113 https://doi.org/10.1007/s11515-014-1302-6
113	Zhao N, Gao J, Enns CA, Knutson MD (2010) ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J Biol Chem 285: 32141-32150 https://doi.org/10.1074/jbc.M110.143248

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