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Translational Therapeutics

HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling

British Journal of Cancer volume 129, pages 222–236 (2023)Cite this article

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Abstract

Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.

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Fig. 1: Schematic representation of liver Hepcidin regulation.
Fig. 2: Interaction between HIF2α and hepcidin in physiological (low and high iron levels) and pathological (cancer) conditions in the intestine.

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The present review has been written using as source articles that are all publicly available.

References

  1. Morales M, Xue X. Targeting iron metabolism in cancer therapy. Theranostics. 2021;11:8412–29.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Hsu MY, Mina E, Roetto A, Porporato PE. Iron: an essential element of cancer metabolism. Cells. 2020;9:2591.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Guo Q, Li L, Hou S, Yuan Z, Li C, Zhang W, et al. The role of iron in cancer progression. Front Oncol. 2021;11:778492.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Doguer C, Ha JH, Collins JF. Intersection of iron and copper metabolism in the mammalian intestine and liver. Compr Physiol. 2018;8:1433–61.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Xu MM, Wang J, Xie JX. Regulation of iron metabolism by hypoxia-inducible factors. Sheng Li Xue Bao. 2017;69:598–610.

    PubMed  Google Scholar 

  6. Ganz T, Nemeth E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematol Am Soc Hematol Educ Program. 2011;2011:538–42.

    Article  Google Scholar 

  7. Jung M, Mertens C, Tomat E, Brüne B. Iron as a central player and promising target in cancer progression. Int J Mol Sci. 2019;20:273.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83–92.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Prabhakar NR, Semenza GL. Oxygen sensing and homeostasis. Physiology. 2015;30:340–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Davis L, Recktenwald M, Hutt E, Fuller S, Briggs M, Goel A, et al. Targeting HIF-2α in the tumor microenvironment: redefining the role of HIF-2α for solid cancer therapy. Cancers. 2022;14:1259.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9:10–7.

    Article  CAS  PubMed  Google Scholar 

  12. Mole DR. Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal. 2010;12:445–58. https://doi.org/10.1089/ars.2009.2790.

    Article  CAS  PubMed  Google Scholar 

  13. Mackenzie B, Garrick MD. Iron Imports. II. Iron uptake at the apical membrane in the intestine. Am J Physiol Gastrointest Liver Physiol. 2005;289:G981–6. https://doi.org/10.1152/ajpgi.00363.2005.

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki N, Yamamoto M. Roles of renal erythropoietin-producing (REP) cells in the maintenance of systemic oxygen homeostasis. Pflug Arch. 2016;468:3–12. https://doi.org/10.1007/s00424-015-1740-2.

    Article  CAS  Google Scholar 

  15. Gammella E, Diaz V, Recalcati S, Buratti P, Samaja M, Dey S, et al. Erythropoietin’s inhibiting impact on hepcidin expression occurs indirectly. Am J Physiol Regul Integr Comp Physiol. 2015;308:R330–5. https://doi.org/10.1152/ajpregu.00410.2014.

    Article  CAS  PubMed  Google Scholar 

  16. Srole DN, Ganz T. Erythroferrone structure, function, and physiology: Iron homeostasis and beyond. J Cell Physiol. 2021;236:4888–901. https://doi.org/10.1002/jcp.30247.

    Article  CAS  PubMed  Google Scholar 

  17. Drakesmith H, Nemeth E, Ganz T. Ironing out ferroportin. Cell Metab. 2015;22:777–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Fisher AL, Babitt JL. Coordination of iron homeostasis by bone morphogenetic proteins: current understanding and unanswered questions. Dev Dyn. 2022;251:26–46. https://doi.org/10.1002/dvdy.372.

    Article  CAS  PubMed  Google Scholar 

  19. Lee DH, Zhou LJ, Zhou Z, Xie JX, Jung JU, Liu Y, et al. Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis. Blood. 2010;115:3136–45. https://doi.org/10.1182/blood-2009-11-251199.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Nemeth E, Ganz T. Hepcidin and iron in health and disease. Annu Rev Med. 2023;74:261–77. https://doi.org/10.1146/annurev-med-043021-032816.

    Article  CAS  PubMed  Google Scholar 

  21. Arezes J, Foy N, McHugh K, Sawant A, Quinkert D, Terraube V, et al. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 2018;132:1473–7. https://doi.org/10.1182/blood-2018-06-857995.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Vela D, Vela-Gaxha Z. Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. Exp Mol Med. 2018;50:e436. https://doi.org/10.1038/emm.2017.273.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Nemeth E, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Yamamoto K, et al. Interplay of adipocyte and hepatocyte: leptin upregulates hepcidin. Biochem Biophys Res Commun. 2018;495:1548–54.

    Article  CAS  PubMed  Google Scholar 

  25. Savarese G, von Haehling S, Butler J, Cleland JGF, Ponikowski P, Anker SD. Iron deficiency and cardiovascular disease. Eur Heart J. 2023;44:14–27. https://doi.org/10.1093/eurheartj/ehac569.

    Article  PubMed  Google Scholar 

  26. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93:1721–41. https://doi.org/10.1152/physrev.00008.2013.

    Article  CAS  PubMed  Google Scholar 

  27. Richardson DR, Kalinowski DS, Lau S, Jansson PJ, Lovejoy DB. Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochim Biophys Acta. 2009;1790:702–17. https://doi.org/10.1016/j.bbagen.2008.04.003.

    Article  CAS  PubMed  Google Scholar 

  28. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.

    Article  CAS  PubMed  Google Scholar 

  29. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.

    Article  CAS  PubMed  Google Scholar 

  30. Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D, et al. Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success. Cancer Cell. 2012;21:52–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S, et al. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood. 2009;114:469–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12:9–22.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Messai Y, Gad S, Noman MZ, Le Teuff G, Couve S, Janji B, et al. Renal cell carcinoma programmed death-ligand 1, a new direct target of hypoxia-inducible factor-2 alpha, is regulated by von Hippel-Lindau gene mutation status. Eur Urol. 2016;70:623–32.

    Article  CAS  PubMed  Google Scholar 

  34. Palazon A, Tyrakis PA, Macias D, Veliça P, Rundqvist H, Fitzpatrick S, et al. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell. 2017;32:669–83.e5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Xie C, Yagai T, Luo Y, Liang X, Chen T, Wang Q, et al. Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis. Nat Med. 2017;23:1298–308.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, et al. HIF2α-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov. 2015;5:652–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Walter KM, Schönenberger MJ, Trötzmüller M, Horn M, Elsässer HP, Moser AB, et al. Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy. Cell Metab. 2014;20:882–97.

    Article  CAS  PubMed  Google Scholar 

  38. Tong WH, Sourbier C, Kovtunovych G, Jeong SY, Vira M, Ghosh M, et al. The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels. Cancer Cell. 2011;20:315–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Dengler VL, Galbraith M, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol. 2014;49:1–15.

    Article  CAS  PubMed  Google Scholar 

  40. Bindra RS, Vasselli JR, Stearman R, Linehan WM, Klausner RD. VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Res. 2002;62:3014–9.

    CAS  PubMed  Google Scholar 

  41. Franovic A, Holterman CE, Payette J, Lee S. Human cancers converge at the HIF-2alpha oncogenic axis. Proc Natl Acad Sci USA. 2009;106:21306–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Sanchez M, Galy B, Muckenthaler MU, Hentze MW. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol. 2007;14:420–6.

    Article  CAS  PubMed  Google Scholar 

  43. Linehan WM, Ricketts CJ. The cancer genome atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol. 2019;16:539–52.

    Article  CAS  PubMed  Google Scholar 

  44. Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine. 1997;76:381–91.

    Article  CAS  PubMed  Google Scholar 

  45. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cells. 2002;1:459–68.

    Article  CAS  Google Scholar 

  46. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, et al. HIFalpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cells. 2008;14:435–46.

    Article  CAS  Google Scholar 

  47. Kondo K, Kim WY, Lechpammer M, Kaelin, Jr WG. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 2003;1:439–44.

    Article  CAS  Google Scholar 

  48. Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxiainducible factor is sufficient for growth suppression of VHL−/− tumors. Mol Cancer Res. 2004;2:89–95.

    Article  CAS  PubMed  Google Scholar 

  49. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cells. 2002;1:237–46.

    Article  CAS  Google Scholar 

  50. Qin S, Li A, Yi M, Yu S, Zhang M, Wu K. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol. 2019;12:27.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Choueiri TK, Kaelin WG Jr. Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med. 2020;26:1519–30.

    Article  CAS  PubMed  Google Scholar 

  52. Navani V, Heng DYC. Treatment selection in first-line metastatic renal cell carcinoma-the contemporary treatment paradigm in the age of combination therapy: a review. JAMA Oncol. 2022;8:292–9.

    Article  PubMed  Google Scholar 

  53. Ferician AM, Ferician OC, Cumpanas AD, Berzava PL, Nesiu A, Barmayoun A, et al. Heterogeneity of platelet derived growth factor pathway gene expression profile defines three distinct subgroups of renal cell carcinomas. Cancer Genom Proteom. 2022;19:477–89.

    Article  CAS  Google Scholar 

  54. Uhlman DL, Nguyen P, Manivel JC, Zhang G, Hagen K, Fraley E, et al. Epidermal growth factor receptor and transforming growth factor alpha expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis. Clin Cancer Res. 1995;1:913–20.

    CAS  PubMed  Google Scholar 

  55. Dawson NA, Guo C, Zak R, Dorsey B, Smoot J, Wong J, et al. A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. Clin Cancer Res. 2004;10:7812–9.

    Article  CAS  PubMed  Google Scholar 

  56. Nakaigawa N, Yao M, Baba M, Kato S, Kishida T, Hattori K, et al. Inactivation of von Hippel-Lindau gene induces constitutive phosphorylation of MET protein in clear cell renal carcinoma. Cancer Res. 2006;66:3699–705.

    Article  CAS  PubMed  Google Scholar 

  57. Chu Q, Han N, Yuan X, Nie X, Wu H, Chen Y, et al. DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells. J Hematol Oncol. 2014;7:73.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z, Du X, et al. A small-molecule antagonist of HIF2α is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76:5491–500.

    Article  CAS  PubMed  Google Scholar 

  59. Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, et al. 3-[(1 S,2 S,3 R)-2,3-difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzo nitrile (PT2977), a hypoxia-inducible factor 2α (HIF-2α) inhibitor for the treatment of clear cell renal cell carcinoma. J. Med. Chem. 2019;62:6876–93.

  60. Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27:802–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for Renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385:2036–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Wei H, Ke HL, Lin J, Shete S, Wood CG, Hildebrandt MA. MicroRNA target site polymorphisms in the VHL-HIF1α pathway predict renal cell carcinoma risk. Mol Carcinog. 2014;53:1–7. https://doi.org/10.1002/mc.21917.

    Article  CAS  PubMed  Google Scholar 

  63. Greene CJ, Attwood K, Sharma NJ, Gross KW, Smith GJ, Xu B, et al. Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients. Oncotarget. 2017;8:107052–75.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Ricchi P, Ammirabile M, Spasiano A, Costantini S, Di Matola T, Cartenì G, et al. Renal cell carcinoma in adult patients with thalassaemia major: a description of three cases. Br J Haematol. 2014;165:887–8.

    Article  PubMed  Google Scholar 

  65. Partanen T, Heikkilä P, Hernberg S, Kauppinen T, Moneta G, Ojajärvi A. Renal cell cancer and occupational exposure to chemical agents. Scand J Work Environ Health. 1991;17:231–9.

    Article  CAS  PubMed  Google Scholar 

  66. Weinberg ED. Tobacco smoke iron: an initiator/promoter of multiple diseases. Biometals. 2009;22:207–10.

    Article  CAS  PubMed  Google Scholar 

  67. Li JL, Okada S, Hamazaki S, Ebina Y, Midorikawa O. Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate. Cancer Res. 1987;47:1867–9.

    CAS  PubMed  Google Scholar 

  68. Ebina Y, Okada S, Hamazaki S, Ogino F, Li JL, Midorikawa O. Nephrotoxicity and renal cell carcinoma after use of iron- and aluminum-nitrilotriacetate complexes in rats. J Natl Cancer Inst. 1986;76:107–13.

    CAS  PubMed  Google Scholar 

  69. Greene CJ, Sharma NJ, Fiorica PN, Forrester E, Smith GJ, Gross KW, et al. Suppressive effects of iron chelation in clear cell renal cell carcinoma and their dependency on VHL inactivation. Free Radic Biol Med. 2019;133:295–309.

    Article  CAS  PubMed  Google Scholar 

  70. Green YS, Ferreira Dos Santos MC, Fuja DG, Reichert EC, Campos AR, Cowman SJ, et al. ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma. Oncogene. 2022. https://doi.org/10.1038/s41388-022-02460-1.

    Article  PubMed Central  PubMed  Google Scholar 

  71. Ramakrishnan SK, Shah YM. Role of intestinal HIF-2α in health and disease. Annu Rev Physiol. 2016;78:301–25.

    Article  CAS  PubMed  Google Scholar 

  72. Xue X, Taylor M, Anderson E, Hao C, Qu A, Greenson JK, et al. Hypoxia-inducible factor-2α activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 2012;72:2285–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Chun SY, Johnson C, Washburn JG, Cruz-Correa MR, Dang DT, Dang LH. Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes. Mol Cancer. 2010;9:293.

    Article  PubMed Central  PubMed  Google Scholar 

  74. Yoshimura H, Dhar DK, Kohno H, Kubota H, Fujii T, Ueda S, et al. Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin Cancer Res. 2004;10:8554–60.

    Article  CAS  PubMed  Google Scholar 

  75. Nijkamp MW, van der Bilt JD, de Bruijn MT, Molenaar IQ, Voest EE, van Diest PJ, et al. Accelerated perinecrotic outgrowth of colorectal liver metastases following radiofrequency ablation is a hypoxia-driven phenomenon. Ann Surg. 2009;249:814–23.

    Article  PubMed  Google Scholar 

  76. Malier M, Gharzeddine K, Laverriere MH, Marsili S, Thomas F, Decaens T, et al. Hypoxia drives dihydropyrimidine dehydrogenase expression in macrophages and confers chemoresistance in colorectal cancer. Cancer Res. 2021;81:5963–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Schito L, Rey S, Xu P, Man S, Cruz-Muñoz W, Kerbel RS. Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers. EMBO Mol Med. 2020;12:e11416.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Singhal R, Mitta SR, Das NK, Kerk SA, Sajjakulnukit P, Solanki S, et al. HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron. J Clin Invest. 2021;131:e143691.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Yan Y, He M, Zhao L, Wu H, Zhao Y, Han L, et al. A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis. Cell Death Differ. 2022. https://doi.org/10.1038/s41418-022-00963-8.

    Article  PubMed Central  PubMed  Google Scholar 

  81. Fu X, Jeselsohn R, Pereira R, Hollingsworth EF, Creighton CJ, Li F, et al. FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci USA. 2016;113:E6600–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Fu X, Pereira R, De Angelis C, Veeraraghavan J, Nanda S, Qin L, et al. FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer. Proc Natl Acad Sci USA. 2019;116:26823–34.

  83. Ströfer M, Jelkmann W, Depping R. Curcumin decreases survival of Hep3B liver and MCF-7 breast cancer cells: the role of HIF. Strahlenther Onkol. 2011;187:393–400.

    Article  PubMed  Google Scholar 

  84. Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, et al. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys. 2000;48:919–22.

    Article  CAS  PubMed  Google Scholar 

  85. Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell. 2017;32:71.e7.

    Article  Google Scholar 

  86. Colbert LE, Fisher SB, Balci S, Saka B, Chen Z, Kim S, et al. High nuclear hypoxia-inducible factor 1 alpha expression is a predictor of distant recurrence in patients with resected pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2015;91:631–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Garcia Garcia CJ, Huang Y, Fuentes NR, Turner MC, Monberg ME, Lin D, et al. Stromal HIF2 regulates immune suppression in the pancreatic cancer microenvironment. Gastroenterology. 2022;162:2018–31.

    Article  CAS  PubMed  Google Scholar 

  88. Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 2020;31:267–83.e12.

    Article  CAS  PubMed  Google Scholar 

  89. Chen R, Lai LA, Sullivan Y, Wong M, Wang L, Riddell J, et al. Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer. Sci Rep. 2017;7:7950.

    Article  PubMed Central  PubMed  Google Scholar 

  90. Zhang Q, Lou Y, Zhang J, Fu Q, Wei T, Sun X, et al. Hypoxia-inducible factor-2α promotes tumor progression and has crosstalk with Wnt/β-catenin signaling in pancreatic cancer. Mol Cancer. 2017;16:119.

    Article  PubMed Central  PubMed  Google Scholar 

  91. Yang J, Zhang X, Zhang Y, Zhu D, Zhang L, et al. HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J Exp Clin Cancer Res. 2016;35:26.

    Article  PubMed Central  PubMed  Google Scholar 

  92. Méndez-Blanco C, Fernández-Palanca P, Fondevila F, González-Gallego J, Mauriz JL. Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis. Ther Adv Med Oncol. 2021;13:1758835920987071.

    Article  PubMed Central  PubMed  Google Scholar 

  93. Llovet JM, Pinyol R, Kelley RK, El-Khoueiry A, Reeves HL, Wang XW, et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat Cancer. 2022;3:386–401.

    Article  PubMed Central  PubMed  Google Scholar 

  94. Cramer T, Vaupel P. Severe hypoxia is a typical characteristic of human hepatocellular carcinoma: scientific fact or fallacy? J Hepatol. 2022;76:975–80.

    Article  CAS  PubMed  Google Scholar 

  95. Younes R, Bugianesi E. Should we undertake surveillance for HCC in patients with NAFLD? J Hepatol. 2018;68:326–34.

    Article  PubMed  Google Scholar 

  96. Foglia B, Sutti S, Cannito S, Rosso C, Maggiora M, Autelli R, et al. Hepatocyte-specific deletion of HIF2α prevents NASH-related liver carcinogenesis by decreasing cancer cell proliferation. Cell Mol Gastroenterol Hepatol. 2022;13:459–82.

    Article  CAS  PubMed  Google Scholar 

  97. Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019;18:163.

    Article  PubMed Central  PubMed  Google Scholar 

  98. Méndez-Blanco C, Fondevila F, García-Palomo A, González-Gallego J, Mauriz JL. Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors. Exp Mol Med. 2018;50:1–9.

    Article  PubMed  Google Scholar 

  99. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10.

    Article  CAS  PubMed  Google Scholar 

  100. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science. 2012;338:768–72.

    Article  CAS  PubMed  Google Scholar 

  101. Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW. Hepcidin in human iron disorders: diagnostic implications. Clin Chem. 2011;57:1650–69.

    Article  CAS  PubMed  Google Scholar 

  102. Mittler R, Darash-Yahana M, Sohn YS, Bai F, Song L, Cabantchik IZ, et al. NEET proteins: a new link between iron metabolism, reactive oxygen species, and cancer. Antioxid Redox Signal. 2019;30:1083–95.

    Article  CAS  PubMed  Google Scholar 

  103. Sacco A, Battaglia AM, Botta C, Aversa I, Mancuso S, Costanzo F, et al. Iron metabolism in the tumor microenvironment-implications for anti-cancer immune response. Cells. 2021;10:303.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Santana-Codina N, Del Rey MQ, Kapner KS, Zhang H, Gikandi A, Malcolm C, et al. NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins. Cancer Discov. 2022;12:2180–97.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Lelièvre P, Sancey L, Coll JL, Deniaud A, Busser B. Iron dysregulation in human cancer: altered metabolism, biomarkers for diagnosis, prognosis, monitoring and rationale for therapy. Cancers. 2020;12:3524.

    Article  PubMed Central  PubMed  Google Scholar 

  106. Le NT, Richardson DR. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta. 2002;1603:31–46.

    CAS  PubMed  Google Scholar 

  107. Xue X, Ramakrishnan SK, Weisz K, Triner D, Xie L, Attili D, et al. Iron uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis. Cell Metab. 2016;24:447–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Brookes MJ, Hughes S, Turner FE, Reynolds G, Sharma N, Ismail T, et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut. 2006;55:1449–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Schwartz AJ, Goyert JW, Solanki S, Kerk SA, Chen B, Castillo C, et al. Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells. Nat Metab. 2021;3:969–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Pinnix ZK, Miller LD, Wang W, D’Agostino R Jr, Kute T, Willingham MC, et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med. 2010;2:43ra56.

    Article  PubMed Central  PubMed  Google Scholar 

  111. Zhang S, Chen Y, Guo W, Yuan L, Zhang D, Xu Y, et al. Disordered hepcidin–ferroportin signaling promotes breast cancer growth. Cell Signal. 2014;26:2539–50.

    Article  CAS  PubMed  Google Scholar 

  112. Orlandi R, De Bortoli M, Ciniselli CM, Vaghi E, Caccia D, Garrisi V, et al. Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer. Ann Oncol. 2014;25:352–7.

    Article  CAS  PubMed  Google Scholar 

  113. Blanchette-Farra N, Kita D, Konstorum A, Tesfay L, Lemler D, Hegde P, et al. Contribution of three-dimensional architecture and tumor-associated fibroblasts to hepcidin regulation in breast cancer. Oncogene. 2018;37:4013–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Villarroel P, Le Blanc S, Arredondo M. Interleukin-6 and lipopolysaccharide modulate hepcidin mRNA expression by HepG2 cells. Biol Trace Elem Res. 2012;150:496–501.

    Article  PubMed  Google Scholar 

  115. Zhao B, Li R, Cheng G, Li Z, Zhang Z, Li J, et al. Role of hepcidin and iron metabolism in the onset of prostate cancer. Oncol Lett. 2018;15:9953–8.

    PubMed Central  PubMed  Google Scholar 

  116. Tesfay L, Clausen KA, Kim JW, Hegde P, Wang X, Miller LD, et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res. 2015;75:2254–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  117. Tanno T, Rabel A, Alleyne M, Lee YT, Dahut WL, Gulley JL, et al. Hepcidin, anaemia, and prostate cancer. B J U Int. 2011;107:678–9.

    Article  Google Scholar 

  118. Wang X, Shi Q, Gong P, Zhou C, Cao Y. An integrated systematic analysis and the clinical significance of hepcidin in common malignancies of the male genitourinary system. Front Genet. 2022;13:771344.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Fan Y, Liu B, Chen F, Song Z, Han B, Meng Y, et al. hepcidin upregulation in lung cancer: a potential therapeutic target associated with immune infiltration. Front Immunol. 2021;12:612144.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Ho T, Nichols M, Nair G, Radford K, Kjarsgaard M, Huang C, et al. Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease. Respir Res. 2022;23:8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Frost JN, Tan TK, Abbas M, Wideman SK, Bonadonna M, Stoffel NU, et al. Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection. Medicine. 2021;2:164–79.e12.

    Article  CAS  Google Scholar 

  122. Brzóska K, Bartłomiejczyk T, Sochanowicz B, Cymerman M, Grudny J, Kołakowski J, et al. Carcinogenesis-related changes in iron metabolism in chronic obstructive pulmonary disease subjects with lung cancer. Oncol Lett. 2018;16:6831–7.

    PubMed Central  PubMed  Google Scholar 

  123. Maegdefrau U, Arndt S, Kivorski G, Hellerbrand C, Bosserhoff AK. Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. Lab Invest. 2011;91:1615–23.

    Article  CAS  PubMed  Google Scholar 

  124. Udali S, Castagna A, Corbella M, Ruzzenente A, Moruzzi S, Mazzi F, et al. Hepcidin and DNA promoter methylation in hepatocellular carcinoma. Eur J Clin Invest. 2018;48:e12870.

    Article  PubMed  Google Scholar 

  125. Kijima H, Sawada T, Tomosugi N, Kubota K. Expression of hepcidin mRNA is uniformly suppressed in hepatocellular carcinoma. BMC Cancer. 2008;8:167.

    Article  PubMed Central  PubMed  Google Scholar 

  126. Kew MC. Hepatic iron overload and hepatocellular carcinoma. Liver Cancer. 2014;3:31–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Rapisarda C, Puppi J, Hughes RD, Dhawan A, Farnaud S, Evans RW, et al. Transferrin receptor 2 is crucial for iron sensing in human hepatocytes. Am J Physiol Gastrointest Liver Physiol. 2010;299:G778–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM. Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences. Exp Biol Med. 2009;234:693–702.

    Article  CAS  Google Scholar 

  129. Worthen CA, Enns CA. The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body. Front Pharmacol. 2014;5:34.

    Article  PubMed Central  PubMed  Google Scholar 

  130. Rishi G, Wallace DF, Subramaniam VN. Hepcidin: regulation of the master iron regulator. Biosci Rep. 2015;35:e00192.

    Article  PubMed Central  PubMed  Google Scholar 

  131. Sangkhae V, Nemeth E. Regulation of the iron homeostatic hormone hepcidin. Adv Nutr. 2017;8:126–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. He Y, Cui Y, Xu B, Gu J, Wang W, Luo X. Hypermethylation leads to bone morphogenetic protein 6 downregulation in hepatocellular carcinoma. PLoS ONE. 2014;9:e87994.

    Article  PubMed Central  PubMed  Google Scholar 

  133. Park WS, Cho YG, Kim CJ, Song JH, Lee YS, Kim SY, et al. Hypermethylation of the RUNX3 gene in hepatocellular carcinoma. Exp Mol Med. 2005;37:276–81.

    Article  CAS  PubMed  Google Scholar 

  134. Weizer-Stern O, Adamsky K, Margalit O, Ashur-Fabian O, Givol D, Amariglio N, et al. Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. Br J Haematol. 2007;138:253–62.

    Article  CAS  PubMed  Google Scholar 

  135. Han CY, Koo JH, Kim SH, Gardenghi S, Rivella S, Strnad P, et al. Hepcidin inhibits Smad3 phosphorylation in hepatic stellate cells by impeding ferroportin-mediated regulation of Akt. Nat Commun. 2016;7:13817.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology. 2012;56:769–75.

    Article  CAS  PubMed  Google Scholar 

  137. Shen Y, Li X, Su Y, Badshah SA, Zhang B, Xue Y, et al. HAMP downregulation contributes to aggressive hepatocellular carcinoma via mechanism mediated by cyclin4-dependent kinase-1/STAT3 pathway. Diagnostics. 2019;9:48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Abd Elmonem E, Tharwa EL-S, Farag MA, Fawzy A, El Shinnawy SF, Suliman S. Hepcidin mRNA level as a parameter of disease progression in chronic hepatitis C and hepatocellular carcinoma. J Egypt Natl Canc Inst. 2009;21:333–42.

    PubMed  Google Scholar 

  139. Burdo JR, Connor JR. Brain iron uptake and homeostatic mechanisms: an overview. Biometals. 2003;16:63–75. https://doi.org/10.1023/a:1020718718550.

    Article  CAS  PubMed  Google Scholar 

  140. Zechel S, Huber-Wittmer K, von Bohlen und Halbach O. Distribution of the iron-regulating protein hepcidin in the murine central nervous system. J Neurosci Res. 2006;84:790–800. https://doi.org/10.1002/jnr.20991.

    Article  CAS  PubMed  Google Scholar 

  141. Hänninen MM, Haapasalo J, Haapasalo H, Fleming RE, Britton RS, Bacon BR, et al. Expression of iron-related genes in human brain and brain tumors. BMC Neurosci. 2009;10:36. https://doi.org/10.1186/1471-2202-10-36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Dong T, Zhang B, Zhang R, Wang C, Liu X, Wang F, et al. Hepcidin is upregulated and is a potential therapeutic target associated with immunity in glioma. Front Oncol. 2022;12:963096. https://doi.org/10.3389/fonc.2022.963096. Erratum in: Front Oncol. 2022 Dec 06;12:1085757.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Hohaus S, Massini G, Giachelia M, Vannata B, Bozzoli V, Cuccaro A, et al. Anemia in Hodgkin’s lymphoma: the role of interleukin-6 and hepcidin. J Clin Oncol. 2010;28:2538–43. https://doi.org/10.1200/JCO.2009.27.6873.

    Article  CAS  PubMed  Google Scholar 

  144. Tisi MC, Bozzoli V, Giachelia M, Massini G, Ricerca BM, Maiolo E, et al. Anemia in diffuse large B-cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin. Leuk Lymphoma. 2014;55:270–5. https://doi.org/10.3109/10428194.2013.802314.

    Article  CAS  PubMed  Google Scholar 

  145. Sharma S, Nemeth E, Chen YH, Goodnough J, Huston A, Roodman GD, et al. Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res. 2008;14:3262–7. https://doi.org/10.1158/1078-0432.CCR-07-4153.

    Article  CAS  PubMed  Google Scholar 

  146. Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood. 2010;116:3635–44. https://doi.org/10.1182/blood-2010-03-274571.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Eisfeld AK, Westerman M, Krahl R, Leiblein S, Liebert UG, Hehme M, et al. Highly elevated serum hepcidin in patients with acute myeloid leukemia prior to and after allogeneic hematopoietic cell transplantation: does this protect from excessive parenchymal iron loading? Adv Hematol. 2011;2011:491058. https://doi.org/10.1155/2011/491058.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  148. Słomka A, Łęcka M, Styczyński J. Hepcidin in children and adults with acute leukemia or undergoing hematopoietic cell transplantation: a systematic review. Cancers. 2022;14:4936. https://doi.org/10.3390/cancers14194936.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Katodritou E, Ganz T, Terpos E, Verrou E, Olbina G, Gastari V, et al. Sequential evaluation of serum hepcidin in anemic myeloma patients: study of correlations with myeloma treatment, disease variables, and anemia response. Am J Hematol. 2009;84:524–6. https://doi.org/10.1002/ajh.21448.

    Article  CAS  PubMed  Google Scholar 

  150. Julián-Serrano S, Yuan F, Wheeler W, Benyamin B, Machiela MJ, Arslan AA, et al. Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies. Am J Clin Nutr. 2021;114:1408–17. https://doi.org/10.1093/ajcn/nqab217.

    Article  PubMed Central  PubMed  Google Scholar 

  151. Toshiyama R, Konno M, Eguchi H, Asai A, Noda T, Koseki J, et al. Association of iron metabolic enzyme hepcidin expression levels with the prognosis of patients with pancreatic cancer. Oncol Lett. 2018;15:8125–33. https://doi.org/10.3892/ol.2018.8357.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Zhou Q, Chen J, Feng J, Wang J. E4BP4 promotes thyroid cancer proliferation by modulating iron homeostasis through repression of hepcidin. Cell Death Dis. 2018;9:987. https://doi.org/10.1038/s41419-018-1001-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Zhang S, Chen Y, Guo W, Yuan L, Zhang D, Xu Y, et al. Disordered hepcidin-ferroportin signaling promotes breast cancer growth. Cell Signal. 2014;26:2539–50. https://doi.org/10.1016/j.cellsig.2014.07.029.

    Article  CAS  PubMed  Google Scholar 

  154. Noguchi-Sasaki M. Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6-producing lung carcinoma cells. BMC Cancer. 2016;16:270. https://doi.org/10.1186/s12885-016-2305-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Pan X, Lu Y, Cheng X, Wang J. Hepcidin and ferroportin expression in breast cancer tissue and serum and their relationship with anemia. Curr Oncol. 2016;23:e24–6. https://doi.org/10.3747/co.23.2840.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Jerzak KJ, Lohmann AE, Ennis M, Nemeth E, Ganz T, Goodwin PJ. Prognostic associations of plasma hepcidin in women with early breast cancer. Breast Cancer Res Treat. 2020;184:927–35. https://doi.org/10.1007/s10549-020-05903-z.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Phillips E. A potential role for hepcidin in obesity-driven colorectal tumourigenesis. Oncol Rep. 2018;39:392–400. https://doi.org/10.3892/or.2017.6062.

    Article  CAS  PubMed  Google Scholar 

  158. Tang Y, Ge S, Zheng X, Zheng J. High Hepcidin expression predicts poor prognosis in patients with clear cell renal cell carcinoma. Diagn Pathol. 2022;17:100. https://doi.org/10.1186/s13000-022-01274-9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Yalovenko TM, Todor IM, Lukianova NY, Chekhun VF. Hepcidin as a possible marker in determination of malignancy degree and sensitivity of breast cancer cells to cytostatic drugs. Exp Oncol. 2016;38:84–8.

    Article  CAS  PubMed  Google Scholar 

  160. Huang J, Liu W, Song S, Li JC, Gan K, Shen C, et al. The iron-modulating hormone hepcidin is upregulated and associated with poor survival outcomes in renal clear cell carcinoma. Front Pharm. 2022;13:1080055. https://doi.org/10.3389/fphar.2022.1080055.

    Article  CAS  Google Scholar 

  161. Qiu H, Gu G, Zuo E, Cheng X. Tumoral overexpression of hepcidin is associated with poor prognosis of patients with clear cell renal cell carcinoma. Cancer Invest. 2023;41:84–92. https://doi.org/10.1080/07357907.2022.2133775.

    Article  CAS  PubMed  Google Scholar 

  162. Sornjai W. Iron and hepcidin mediate human colorectal cancer cell growth. Chem Biol Interact. 2020;319:109021. https://doi.org/10.1016/j.cbi.2020.109021.

    Article  CAS  PubMed  Google Scholar 

  163. Xiang-Tao P. Expression of Hepcidin and Neogenin in Colorectal Cancer. Open Med. 2017;12:184–8. https://doi.org/10.1515/med-2017-0027.

    Article  CAS  Google Scholar 

  164. Zhou Z, Wu J, Yang Y, Gao P, Wang L, Wu Z. Hepcidin as a prognostic biomarker in clear cell renal cell carcinoma. Am J Cancer Res. 2022;12:4120–39.

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Wang F. Hepcidin and iron metabolism in the pathogenesis of prostate cancer. J BUON. 2017;22:1328–32.

    PubMed  Google Scholar 

  166. Di Grazia A, Di Fusco D, Franzè E, Colella M, Strimpakos G, Salvatori S, et al. Hepcidin upregulation in colorectal cancer associates with accumulation of regulatory macrophages and epithelial-mesenchymal transition and correlates with progression of the disease. Cancers. 2022;14:5294. https://doi.org/10.3390/cancers14215294.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. van der Vorm LN, Hendriks JC, Laarakkers CM, Klaver S, Armitage AE, Bamberg A, et al. Toward worldwide hepcidin assay harmonization: identification of a commutable secondary reference material. Clin Chem. 2016;62:993–1001. https://doi.org/10.1373/clinchem.2016.256768.

    Article  CAS  PubMed  Google Scholar 

  168. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol. 2002;20:42–51. https://doi.org/10.1200/JCO.2002.20.1.42.

    Article  CAS  PubMed  Google Scholar 

  169. Traeger L. Serum Hepcidin and GDF-15 levels as prognostic markers in urothelial carcinoma of the upper urinary tract and renal cell carcinoma. BMC Cancer. 2019;19:74. https://doi.org/10.1186/s12885-019-5278-0.

    Article  PubMed Central  PubMed  Google Scholar 

  170. El-Mahdy RI. Circulating osteocyte-related biomarkers (vitamin D, sclerostin, dickkopf-1), hepcidin, and oxidative stress markers in early breast cancer: their impact in disease progression and outcome. J Steroid Biochem Mol Biol. 2020;204:105773. https://doi.org/10.1016/j.jsbmb.2020.105773.

    Article  CAS  PubMed  Google Scholar 

  171. Durigova A. Anemia and iron biomarkers in patients with early breast cancer. Diagnostic value of hepcidin and soluble transferrin receptor quantification. Clin Chem Lab Med. 2013;51:1833–41. https://doi.org/10.1515/cclm-2013-0031.

    Article  CAS  PubMed  Google Scholar 

  172. Wadowska K. Hepcidin as a diagnostic biomarker in anaemic lung cancer patients. Cancers. 2022;15:224. https://doi.org/10.3390/cancers15010224.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Schwartz AJ, Das NK, Ramakrishnan SK, Jain C, Jurkovic MT, Wu J, et al. Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. J Clin Invest. 2019;129:336–48.

    Article  PubMed  Google Scholar 

  174. Lee FS. At the crossroads of oxygen and iron sensing: hepcidin control of HIF-2α. J Clin Invest. 2019;129:72–4.

    Article  PubMed  Google Scholar 

  175. Hawula ZJ, Wallace DF, Subramaniam VN, Rishi G. Therapeutic advances in regulating the hepcidin/ferroportin axis. Pharmaceuticals. 2019;12:170. https://doi.org/10.3390/ph12040170.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Yeh KY, Yeh M, Polk P, Glass J. Hypoxia-inducible factor-2α and iron absorptive gene expression in Belgrade rat intestine. Am J Physiol Gastrointest Liver Physiol. 2011;301:G82–90. https://doi.org/10.1152/ajpgi.00538.2010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Mastrogiannaki M, Matak P, Delga S, Deschemin JC, Vaulont S, Peyssonnaux C. Deletion of HIF-2α in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice. Blood. 2012;119:587–90.

    Article  CAS  PubMed  Google Scholar 

  178. Mastrogiannaki M, Matak P, Peyssonnaux C. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood. 2013;122:885–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  179. Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 2009;119:1159–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  180. Simpson RJ, McKie AT. Regulation of intestinal iron absorption: the mucosa takes control? Cell Metab. 2009;10:84–7.

    Article  CAS  PubMed  Google Scholar 

  181. Ogawa C, Tsuchiya K, Maeda K. Hypoxia-inducible factor prolyl hydroxylase inhibitors and iron metabolism. Int J Mol Sci. 2023;24:3037. https://doi.org/10.3390/ijms24033037.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  182. Liu Q, Davidoff O, Niss K, Haase VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest. 2012;122:4635–44. https://doi.org/10.1172/JCI63924.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  183. Yook JS, You M, Kim J, Toney AM, Fan R, Puniya BL, et al. Essential role of systemic iron mobilization and redistribution for adaptive thermogenesis through HIF2-α/hepcidin axis. Proc Natl Acad Sci USA. 2021;118:e2109186118.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  184. Wilkinson N, Pantopoulos K. IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation. Blood. 2013;122:1658–68.

    Article  CAS  PubMed  Google Scholar 

  185. Laitala A, Aro E, Walkinshaw G, Mäki JM, Rossi M, Heikkilä M, et al. Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis. Blood. 2012;120:3336–44.

    Article  CAS  PubMed  Google Scholar 

  186. Gordeuk VR, Miasnikova GY, Sergueeva AI, Niu X, Nouraie M, Okhotin DJ, et al. Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression. Blood. 2011;118:5278–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Singh AK, Carroll K, Perkovic V, Solomon S, Jha V, Johansen KL, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385:2325–35.

    Article  CAS  PubMed  Google Scholar 

  188. Eckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384:1601–12.

    Article  CAS  PubMed  Google Scholar 

  189. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019;381:1011–22.

    Article  CAS  PubMed  Google Scholar 

  190. Requena-Ibáñez JA, Santos-Gallego CG, Rodriguez-Cordero A, Zafar MU, Badimon JJ. Prolyl hydroxylase inhibitors: a new opportunity in renal and myocardial protection. Cardiovasc Drugs Ther. 2021. https://doi.org/10.1007/s10557-021-07257-0

    Article  PubMed  Google Scholar 

  191. Del Balzo U, Signore PE, Walkinshaw G, Seeley TW, Brenner MC, Wang Q, et al. Nonclinical characterization of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat, a novel treatment of anemia of chronic kidney disease. J Pharmacol Exp Ther. 2020;374:342–53.

    Article  PubMed  Google Scholar 

  192. Landau D, London L, Bandach I, Segev Y. The hypoxia inducible factor/erythropoietin (EPO)/EPO receptor pathway is disturbed in a rat model of chronic kidney disease related anemia. PLoS ONE. 2018;13:e0196684.

    Article  PubMed Central  PubMed  Google Scholar 

  193. Estrela GR, Freitas-Lima LC, Budu A, Arruda AC, Perilhão MS, Fock RA, et al. Chronic kidney disease induced by cisplatin, folic acid and renal ischemia reperfusion induces anemia and promotes GATA-2 activation in mice. Biomedicines. 2021;9:769.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology. 2008;48:1420–9.

    Article  CAS  PubMed  Google Scholar 

  195. Ward DG, Roberts K, Brookes MJ, Joy H, Martin A, Ismail T, et al. Increased hepcidin expression in colorectal carcinogenesis. World J Gastroenterol. 2008;14:1339–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Bregolat NF, Ruetten M, Da Silva MC, Aboouf MA, Ademi H, Büren NV, et al. Iron- and erythropoietin-resistant anemia in a spontaneous breast cancer mouse model. Haematologica. 2022;107:2454–65. https://doi.org/10.3324/haematol.2022.280732.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  197. Vadhan-Raj S, Abonour R, Goldman JW, Smith DA, Slapak CA, Ilaria RL Jr, et al. A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia. J Hematol Oncol. 2017;10:73. https://doi.org/10.1186/s13045-017-0427-x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  198. Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36:867–74. https://doi.org/10.1200/JCO.2017.74.2627.

    Article  CAS  PubMed  Google Scholar 

  199. McDermott DF, Choueiri TK, Tykodi S, et al. Phase II study of belzutifan plus cabozantinib for previously treated advanced renal cell carcinoma (RCC): update from cohort 2 of LITESPARK-003. Ann Oncol. 2022;33:S1208–9.

    Article  Google Scholar 

  200. Pelle E, Al-Toubah T, Morse B, Strosberg J. Belzutifan in a patient with VHL-associated metastatic pancreatic neuroendocrine tumor. J Natl Compr Canc Netw. 2022;20:1285–7. https://doi.org/10.6004/jnccn.2022.7047.

    Article  CAS  PubMed  Google Scholar 

  201. Kamihara J, Hamilton KV, Pollard JA, Clinton CM, Madden JA, Lin J, et al. Belzutifan, a potent HIF2α inhibitor, in the Pacak-Zhuang syndrome. N Engl J Med. 2021;385:2059–65. https://doi.org/10.1056/NEJMoa2110051.

    Article  CAS  PubMed  Google Scholar 

  202. Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, et al. FDA approval summary: belzutifan for von Hippel-Lindau disease-associated tumors. Clin Cancer Res. 2022;28:4843–8. https://doi.org/10.1158/1078-0432.CCR-22-1054.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Motzer RJ, Schmidinger M, Eto M, Suarez C, Figlin R, Liu Y, et al. LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Future Oncol. 2023. https://doi.org/10.2217/fon-2022-0802.

    Article  PubMed  Google Scholar 

  204. Ibrahim O, O’Sullivan J. Iron chelators in cancer therapy. Biometals. 2020;33:201–15. https://doi.org/10.1007/s10534-020-00243-3.

    Article  CAS  PubMed  Google Scholar 

  205. Kunos CA, Andrews SJ, Moore KN, Chon HS, Ivy SP. Randomized phase ii trial of triapine-cisplatin-radiotherapy for locally advanced stage uterine cervix or vaginal cancers. Front Oncol. 2019;9:1067. https://doi.org/10.3389/fonc.2019.01067.

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy

    Vincenzo Formica, Silvia Riondino, Cristina Morelli, Simona Guerriero, Federica D’Amore & Mario Roselli

  2. PhD Program in Systems and Experimental Medicine (XXXV cycle), University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy

    Cristina Morelli

  3. Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy

    Antonio Di Grazia, Giovanna Del Vecchio Blanco & Giovanni Monteleone

  4. Department of Surgery, University of Rome Tor Vergata, Rome, Italy

    Giuseppe Sica

  5. Drug Development Unit, Sarah Cannon Research Institute UK, London, UK

    Hendrik-Tobias Arkenau

Authors
  1. Vincenzo Formica
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  2. Silvia Riondino
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  9. Hendrik-Tobias Arkenau
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  10. Giovanni Monteleone
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  11. Mario Roselli
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Contributions

VF conceived and designed the work that led to the submission, acquired the data, played an important role in interpreting the literature data, drafted and revised the manuscript, approved the final version, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SR, CM and HTA acquired the data, played an important role in interpreting the literature data, revised the manuscript, approved the final version, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SG, FDA, ADG, GDVB, GS, GM and MR played an important role in interpreting the literature data, revised the manuscript, approved the final version, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Vincenzo Formica.

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Formica, V., Riondino, S., Morelli, C. et al. HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling. Br J Cancer 129, 222–236 (2023). https://doi.org/10.1038/s41416-023-02266-2

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