No Access

Control of Iron Availability in Cancer by MicroRNAs

Kamesh R. Babu

Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore

Search for more papers by this author

and

Lei Sun

Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore

Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore

E-mail Address: sun.lei@duke-nus.edu.sg

Corresponding author.

Search for more papers by this author

https://doi.org/10.1142/S2591722620400050Cited by:0 (Source: Crossref)

Abstract

Iron is an essential nutrient required for normal cellular functions, growth, and proliferation. Iron homeostasis is maintained at the cellular and systemic levels by strict regulation of genes involved in the process of iron uptake, storage, export, and surveillance of iron levels. Cellular iron homeostasis is dysregulated in cancer to sustain rapid growth and proliferation. Cellular iron levels are increased in cancer by manipulating the expression of genes involved in iron metabolism. Recent studies show that a class of small non-coding RNA known as microRNA (miRNA) play a major role in the control of iron metabolism. This review summarizes the significance of iron in cancer prognosis and how miRNAs regulate the expression of genes involved in iron metabolism to increase the cellular iron availability in cancer.

Keywords:

References

1. D. P. Bartel, Metazoan microRNAs, Cell 173 2018) 20–51, https://doi.org/10.1016/j.cell.2018.03.006. Crossref, Google Scholar
2. Y. Lee et al., MicroRNA genes are transcribed by RNA polymerase II, The EMBO Journal 23 (2004) 4051–4060, https://doi.org/10.1038/sj.emboj.7600385. Crossref, Google Scholar
3. G. M. Borchert, W. Lanier and B. L. Davidson, RNA polymerase III transcribes human microRNAs, Nature Structural & Molecular Biology 13 (2006) 1097–1101, https://doi.org/10.1038/nsmb1167. Crossref, Google Scholar
4. P. Ramalingam et al., Biogenesis of intronic miRNAs located in clusters by independent transcription and alternative splicing, RNA 20 (2014) 76–87, https://doi.org/10.1261/rna.041814.113. Crossref, Google Scholar
5. T. A. Nguyen et al., Functional anatomy of the human microprocessor, Cell 161 (2015) 1374–1387, https://doi.org/10.1016/j.cell.2015.05.010. Crossref, Google Scholar
6. E. Lund, S. Guttinger, A. Calado, J. E. Dahlberg and U. Kutay, Nuclear export of microRNA precursors, Science 303 (2004) 95–98, https://doi.org/10.1126/science.1090599. Crossref, Google Scholar
7. G. Hutvagner et al., A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA, Science 293 (2001) 834–838, https://doi.org/10.1126/science.1062961. Crossref, Google Scholar
8. S. Iwasaki et al., Hsc70/Hsp90 chaperone machinery mediates ATP-dependent RISC loading of small RNA duplexes, Molecular Cell 39 (2010) 292–299, https://doi.org/10.1016/j.molcel.2010.05.015. Crossref, Google Scholar
9. T. Kawamata and Y. Tomari, Making RISC, Trends in Biochemical Sciences 35 (2010) 368–376, https://doi.org/10.1016/j.tibs.2010.03.009. Crossref, Google Scholar
10. A. R. Bassett et al., Understanding functional miRNA-target interactions in vivo by site-specific genome engineering, Nature Communications 5 (2014) 4640, https://doi.org/10.1038/ncomms5640. Crossref, Google Scholar
11. D. P. Bartel, MicroRNAs: Target recognition and regulatory functions, Cell 136 (2009) 215–233, https://doi.org/10.1016/j.cell.2009.01.002. Crossref, Google Scholar
12. L. Wu, J. Fan and J. G. Belasco, MicroRNAs direct rapid deadenylation of mRNA, Proceedings of the National Academy of Sciences of the United States of America 103 (2006) 4034–4039, https://doi.org/10.1073/pnas.0510928103. Crossref, Google Scholar
13. G. Meister, miRNAs get an early start on translational silencing, Cell 131 (2007) 25–28, https://doi.org/10.1016/j.cell.2007.09.021. Crossref, Google Scholar
14. A. Valinezhad Orang, R. Safaralizadeh and M. Kazemzadeh-Bavili, Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation, International Journal of Genomics 2014 (2014) 970607, https://doi.org/10.1155/2014/970607. Crossref, Google Scholar
15. A. Kozomara, M. Birgaoanu and S. Griffiths-Jones, miRBase: From microRNA sequences to function, Nucleic Acids Research 47 (2019) D155–D162, https://doi.org/10.1093/nar/gky1141. Crossref, Google Scholar
16. R. C. Friedman, K. K. Farh, C. B. Burge and D. P. Bartel, Most mammalian mRNAs are conserved targets of microRNAs, Genome Research 19 (2009) 92–105, https://doi.org/10.1101/gr.082701.108. Crossref, Google Scholar
17. E. Bernstein et al., Dicer is essential for mouse development, Nature Genetics 35 (2003) 215–217, https://doi.org/10.1038/ng1253. Crossref, Google Scholar
18. L. C. Laurent et al., Comprehensive microRNA profiling reveals a unique human embryonic stem cell signature dominated by a single seed sequence, Stem Cells 26 (2008) 1506–1516, https://doi.org/10.1634/stemcells.2007-1081. Crossref, Google Scholar
19. C. T. Neilsen, G. J. Goodall and C. P. Bracken, IsomiRs–the overlooked repertoire in the dynamic microRNAome, Trends in Genetics: TIG 28 (2012) 544–549, https://doi.org/10.1016/j.tig.2012.07.005. Crossref, Google Scholar
20. G. C. Tan et al., 5’ isomiR variation is of functional and evolutionary importance, Nucleic Acids research 42 (2014) 9424–9435, https://doi.org/10.1093/nar/gku656. Crossref, Google Scholar
21. Y. Tay, J. Rinn and P. P. Pandolfi, The multilayered complexity of ceRNA crosstalk and competition, Nature 505 (2014) 344–352, https://doi.org/10.1038/nature12986. Crossref, Google Scholar
22. Y. Peng and C. M. Croce, The role of MicroRNAs in human cancer, Signal Transduction and Targeted Therapy 1 (2016) 15004, https://doi.org/10.1038/sigtrans.2015.4. Crossref, Google Scholar
23. S. S. Zhou et al., miRNAS in cardiovascular diseases: Potential biomarkers, therapeutic targets and challenges, Acta Pharmacologica Sinica 39 (2018) 1073–1084, https://doi.org/10.1038/aps.2018.30. Crossref, Google Scholar
24. J. Feng, W. Xing and L. Xie, Regulatory roles of microRNAs in diabetes, International Journal of Molecular Sciences 17 (2016), https://doi.org/10.3390/ijms17101729. Crossref, Google Scholar
25. D. Li et al., Effect of regulatory network of exosomes and microRNAs on neurodegenerative diseases, Chinese Medical Journal 131 (2018) 2216–2225, https://doi.org/10.4103/0366-6999.240817. Crossref, Google Scholar
26. W. Si, J. Shen, H. Zheng and W. Fan, The role and mechanisms of action of microRNAs in cancer drug resistance, Clinical Epigenetics 11 (2019) 25, https://doi.org/10.1186/s13148-018-0587-8. Crossref, Google Scholar
27. K. Van Roosbroeck and G. A. Calin, Cancer hallmarks and microRNAs: The therapeutic connection, Advances in Cancer Research 135 (2017) 119–149, https://doi.org/10.1016/bs.acr.2017.06.002. Crossref, Google Scholar
28. S. Volinia et al., A microRNA expression signature of human solid tumors defines cancer gene targets, Proceedings of the National Academy of Sciences of the United States of America 103 (2006) 2257–2261, https://doi.org/10.1073/pnas.0510565103. Crossref, Google Scholar
29. G. A. Calin et al., A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia, The New England Journal of Medicine 353 (2005) 1793–1801, https://doi.org/10.1056/NEJMoa050995. Crossref, Google Scholar
30. R. R. Crichton, Iron Metabolism: From Molecular Mechanisms to Clinical Consequences (2016). Crossref, Google Scholar
31. J. J. Braymer and R. Lill, Iron-sulfur cluster biogenesis and trafficking in mitochondria, The Journal of Biological Chemistry 292 (2017) 12754–12763, https://doi.org/10.1074/jbc.R117.787101. Crossref, Google Scholar
32. S. S. Mansy and J. A. Cowan, Iron-sulfur cluster biosynthesis: Toward an understanding of cellular machinery and molecular mechanism, Accounts of Chemical Research 37 (2004) 719–725, https://doi.org/10.1021/ar0301781. Crossref, Google Scholar
33. U. Brandt, Energy converting NADH: Quinone oxidoreductase (complex I), Annual Review of Biochemistry 75 (2006) 69–92, https://doi.org/10.1146/annurev.biochem.75.103004.142539. Crossref, Google Scholar
34. S. Puig, L. Ramos-Alonso, A. M. Romero and M. T. Martinez-Pastor, The elemental role of iron in DNA synthesis and repair, Metallomics: Integrated Biometal Science 9 (2017) 1483–1500, https://doi.org/10.1039/c7mt00116a. Crossref, Google Scholar
35. R. S. Ajioka, J. D. Phillips and J. P. Kushner, Biosynthesis of heme in mammals, Biochimica et Biophysica Acta 1763 (2006) 723–736, https://doi.org/10.1016/j.bbamcr.2006.05.005. Crossref, Google Scholar
36. O. Khalimonchuk and G. Rodel, Biogenesis of cytochrome c oxidase, Mitochondrion 5 (2005) 363–388, https://doi.org/10.1016/j.mito.2005.08.002. Crossref, Google Scholar
37. A. Bilska-Wilkosz, M. Iciek, M. Gorny and D. Kowalczyk-Pachel, The role of hemoproteins: Hemoglobin, myoglobin and neuroglobin in endogenous thiosulfate production processes, International Journal of Molecular Sciences 18 (2017), https://doi.org/10.3390/ijms18061315. Crossref, Google Scholar
38. M. Faller, M. Matsunaga, S. Yin, J. A. Loo and F. Guo, Heme is involved in microRNA processing, Nature Structural & Molecular Biology 14 (2007) 23–29, https://doi.org/10.1038/nsmb1182. Crossref, Google Scholar
39. I. Barr et al., Ferric, not ferrous, heme activates RNA-binding protein DGCR8 for primary microRNA processing, Proceedings of the National Academy of Sciences of the United States of America 109 (2012) 1919–1924, https://doi.org/10.1073/pnas.1114514109. Crossref, Google Scholar
40. Y. Li et al., Iron homeostasis regulates the activity of the microRNA pathway through poly(C)-binding protein 2, Cell Metabolism 15 (2012) 895–904, https://doi.org/10.1016/j.cmet.2012.04.021. Crossref, Google Scholar
41. H. Gunshin et al., Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver, The Journal of Clinical Investigation 115 (2005) 1258–1266, https://doi.org/10.1172/JCI24356. Crossref, Google Scholar
42. A. T. McKie et al., An iron-regulated ferric reductase associated with the absorption of dietary iron, Science 291 (2001) 1755–1759, https://doi.org/10.1126/science.1057206. Crossref, Google Scholar
43. I. Theurl et al., On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver, Nature Medicine 22 (2016) 945–951, https://doi.org/10.1038/nm.4146. Crossref, Google Scholar
44. D. Meynard, J. L. Babitt and H. Y. Lin, The liver: Conductor of systemic iron balance, Blood 123 (2014) 168–176, https://doi.org/10.1182/blood-2013-06-427757. Crossref, Google Scholar
45. T. Ganz, Systemic iron homeostasis, Physiological Reviews 93 (2013) 1721–1741, https://doi.org/10.1152/physrev.00008.2013. Crossref, Google Scholar
46. H. Drakesmith, E. Nemeth and T. Ganz, Ironing out ferroportin, Cell Metabolism 22 (2015) 777–787, https://doi.org/10.1016/j.cmet.2015.09.006. Crossref, Google Scholar
47. B. Qiao et al., Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination, Cell Metabolism 15 (2012) 918–924, https://doi.org/10.1016/j.cmet.2012.03.018. Crossref, Google Scholar
48. S. L. Ross et al., Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT, Cell Metabolism 15 (2012) 905–917, https://doi.org/10.1016/j.cmet.2012.03.017. Crossref, Google Scholar
49. M. U. Muckenthaler, S. Rivella, M. W. Hentze and B. Galy, A red carpet for iron metabolism, Cell 168 (2017) 344–361, https://doi.org/10.1016/j.cell.2016.12.034. Crossref, Google Scholar
50. B. Galy et al., Iron regulatory proteins control a mucosal block to intestinal iron absorption, Cell Reports 3 (2013) 844–857, https://doi.org/10.1016/j.celrep.2013.02.026. Crossref, Google Scholar
51. A. A. Salahudeen et al., An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis, Science 326 (2009) 722–726, https://doi.org/10.1126/science.1176326. Crossref, Google Scholar
52. A. A. Vashisht et al., Control of iron homeostasis by an iron-regulated ubiquitin ligase, Science 326 (2009) 718–721, https://doi.org/10.1126/science.1176333. Crossref, Google Scholar
53. J. W. Thompson et al., Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5), The Journal of Biological Chemistry 287 (2012) 7357–7365, https://doi.org/10.1074/jbc.M111.308684. Crossref, Google Scholar
54. J. A. Campbell, Effects of precipitated silica and of iron oxide on the incidence of primary lung tumours in mice, British Medical Journal 2 (1940) 275–280. Crossref, Google Scholar
55. S. Toyokuni, Role of iron in carcinogenesis: Cancer as a ferrotoxic disease, Cancer Sci 100 (2009) 9–16, https://doi.org/10.1111/j.1349-7006.2008.01001.x. Crossref, Google Scholar
56. N. M. Bastide et al., A central role for heme iron in colon carcinogenesis associated with red meat intake, Cancer Research 75 (2015) 870–879, https://doi.org/10.1158/0008-5472.CAN-14-2554. Crossref, Google Scholar
57. S. Toyokuni, T. Mori and M. Dizdaroglu, DNA base modifications in renal chromatin of Wistar rats treated with a renal carcinogen, ferric nitrilotriacetate, International Journal of Cancer 57 (1994) 123–128. Crossref, Google Scholar
58. S. Akatsuka et al., Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer, PLOS ONE 7 (2012) e43403, https://doi.org/10.1371/journal.pone.0043403. Crossref, Google Scholar
59. S. Radulescu et al., Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo, Cell Reports 17 (2016) 2805–2807, https://doi.org/10.1016/j.celrep.2016.10.028. Crossref, Google Scholar
60. G. Y. Lui et al., The iron chelator, deferasirox, as a novel strategy for cancer treatment: Oral activity against human lung tumor xenografts and molecular mechanism of action, Molecular Pharmacology 83 (2013) 179–190, https://doi.org/10.1124/mol.112. 081893. Crossref, Google Scholar
61. Y. Yu, Z. Kovacevic and D. R. Richardson, Tuning cell cycle regulation with an iron key, Cell Cycle 6 (2007) 1982–1994, https://doi.org/10.4161/cc.6.16.4603. Crossref, Google Scholar
62. S. Nagata, Apoptosis and clearance of apoptotic cells, Annual Review of Immunology 36 (2018) 489–517, https://doi.org/10.1146/annurev-immunol-042617-053010. Crossref, Google Scholar
63. R. A. Cairns, I. S. Harris and T. W. Mak, Regulation of cancer cell metabolism, Nature Reviews. Cancer 11 (2011) 85–95, https://doi.org/10.1038/nrc2981. Crossref, Google Scholar
64. J. Wang et al., The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway, Oncotarget 5 (2014) 8478–8491, https://doi.org/10.18632/oncotarget.2328. Crossref, Google Scholar
65. W. Guo et al., An important role of the hepcidin-ferroportin signaling in affecting tumor growth and metastasis, Acta Biochimica et Biophysica Sinica 47 (2015) 703–715, https://doi.org/10.1093/abbs/gmv063. Crossref, Google Scholar
66. J. Sun et al., Targeting the metastasis suppressor, NDRG1, using novel iron chelators: Regulation of stress fiber-mediated tumor cell migration via modulation of the ROCK1/pMLC2 signaling pathway, Molecular Pharmacology 83 (2013) 454–469, https://doi.org/10.1124/mol.112.083097. Crossref, Google Scholar
67. D. Basuli et al., Iron addiction: A novel therapeutic target in ovarian cancer, Oncogene 36 (2017) 4089–4099, https://doi.org/10.1038/onc.2017.11. Crossref, Google Scholar
68. Z. Chen et al., The iron chelators Dp44mT and DFO inhibit TGF-beta-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1), The Journal of Biological Chemistry 287 (2012) 17016–17028, https://doi.org/10.1074/jbc.M112.350470. Crossref, Google Scholar
69. Z. J. Wang, K. W. Lam, T. T. Lam and M. O. Tso, Iron-induced apoptosis in the photoreceptor cells of rats, Investigative Ophthalmology & Visual Science 39 (1998) 631–633. Google Scholar
70. C. Velez-Pardo, M. Jimenez Del Rio, H. Verschueren, G. Ebinger and G. Vauquelin, Dopamine and iron induce apoptosis in PC12 cells, Pharmacology & Toxicology 80 (1997) 76–84. Crossref, Google Scholar
71. V. E. Kagan et al., Cytochrome c/cardiolipin relations in mitochondria: A kiss of death, Free Radical Biology & Medicine 46 (2009) 1439–1453, https://doi.org/10.1016/j.freeradbiomed.2009.03.004. Crossref, Google Scholar
72. J. E. Ricci et al., Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain, Cell 117 (2004) 773–786, https://doi.org/10.1016/j.cell.2004.05.008. Crossref, Google Scholar
73. M. C. Dai et al., Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis, Neuroscience Letters 536 (2013) 41–46, https://doi.org/10.1016/j.neulet.2013.01.007. Crossref, Google Scholar
74. L. Galluzzi, O. Kepp, F. K. Chan and G. Kroemer, Necroptosis: Mechanisms and relevance to disease, Annual Review of Pathology 12 (2017) 103–130, https://doi.org/10.1146/annurev-pathol-052016-100247. Crossref, Google Scholar
75. F. Basit et al., Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells, Cell Death & Disease 8 (2017) e2716, https://doi.org/10.1038/cddis.2017.133. Crossref, Google Scholar
76. S. J. Dixon et al., Ferroptosis: An iron-dependent form of nonapoptotic cell death, Cell 149 (2012) 1060–1072, https://doi.org/10.1016/j.cell.2012.03.042. Crossref, Google Scholar
77. H. Feng and B. R. Stockwell, Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLOS Biology 16 (2018) e2006203, https://doi.org/10.1371/journal.pbio.2006203. Crossref, Google Scholar
78. E. Gammella, S. Recalcati and G. Cairo, Dual role of ROS as signal and stress agents: Iron tips the balance in favor of toxic effects, Oxidative Medicine and Cellular Longevity 2016 (2016) 8629024, https://doi.org/10.1155/2016/8629024. Crossref, Google Scholar
79. S. NavaneethaKrishnan, J. L. Rosales and K. Y. Lee, ROS-mediated cancer cell killing through dietary phytochemicals, Oxidative Medicine and Cellular Longevity 2019 (2019) 9051542, https://doi.org/10.1155/2019/9051542. Crossref, Google Scholar
80. K. R. Babu and Y. Tay, The Yin-Yang regulation of reactive oxygen species and microRNAs in cancer, International Journal of Molecular Sciences 20 (2019), https://doi.org/10.3390/ijms20215335. Crossref, Google Scholar
81. E. Nemeth and T. Ganz, Anemia of inflammation, Hematology/Oncology Clinics of North America 28 (2014) 671–681, vi, https://doi.org/10.1016/j.hoc.2014.04.005. Crossref, Google Scholar
82. I. Buck, F. Morceau, C. Grigorakaki, M. Dicato and M. Diederich, Linking anemia to inflammation and cancer: The crucial role of TNFalpha, Biochemical Pharmacology 77 (2009) 1572–1579, https://doi.org/10.1016/j.bcp.2008.12.018. Crossref, Google Scholar
83. P. Aisen, A. Leibman and J. Zweier, Stoichiometric and site characteristics of the binding of iron to human transferrin, The Journal of Biological Chemistry 253 (1978) 1930–1937. Crossref, Google Scholar
84. R. S. Ohgami et al., Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells, Nature Genetics 37 (2005) 1264–1269, https://doi.org/10.1038/ng1658. Crossref, Google Scholar
85. T. R. Daniels et al., The transferrin receptor and the targeted delivery of therapeutic agents against cancer, Biochimica et Biophysica Acta 1820 (2012) 291–317, https://doi.org/10.1016/j.bbagen.2011. 07.016. Crossref, Google Scholar
86. K. R. Babu and M. U. Muckenthaler, miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma, Scientific Reports 9 (2019) 1518, https://doi.org/10.1038/s41598-018-35947-7. Crossref, Google Scholar
87. I. Kindrat et al., MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis, Oncotarget 7 (2016) 1276–1287, https://doi.org/10.18632/oncotarget.6004. Crossref, Google Scholar
88. M. Miyazawa, A. R. Bogdan, K. Hashimoto and Y. Tsuji, Regulation of transferrin receptor-1 mRNA by the interplay between IRE-binding proteins and miR-7/miR-141 in the 3’-IRE stem-loops, RNA 24 (2018) 468–479, https://doi.org/10.1261/rna.063941.117. Crossref, Google Scholar
89. D. G. Schaar, D. J. Medina, D. F. Moore, R. K. Strair and Y. Ting, miR-320 targets transferrin receptor 1 (CD71) and inhibits cell proliferation, Experimental Hematology 37 (2009) 245–255, https://doi.org/10.1016/j.exphem.2008.10.002. Crossref, Google Scholar
90. Y. Yoshioka, N. Kosaka, T. Ochiya and T. Kato, Micromanaging iron homeostasis: Hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins, The Journal of Biological Chemistry 287 (2012) 34110–34119, https://doi.org/10.1074/jbc.M112.356717. Crossref, Google Scholar
91. Y. A. Suzuki, V. Lopez and B. Lonnerdal, Mammalian lactoferrin receptors: Structure and function, Cellular and Molecular Life Sciences (CMLS) 62 (2005) 2560–2575, https://doi.org/10.1007/s00018-005-5371-1. Crossref, Google Scholar
92. Y. Liao, X. Du and B. Lonnerdal, miR-214 regulates lactoferrin expression and pro-apoptotic function in mammary epithelial cells, The Journal of Nutrition 140 (2010) 1552–1556, https://doi.org/10.3945/jn.110.124289. Crossref, Google Scholar
93. Y. Tao et al., MiR-214-3p regulates the viability, invasion, migration and EMT of TNBC cells by targeting ST6GAL1, Cytotechnology 71 (2019) 1155–1165, https://doi.org/10.1007/s10616-019-00352-z. Crossref, Google Scholar
94. Y. Liao and B. Lonnerdal, miR-584 mediates post-transcriptional expression of lactoferrin receptor in Caco-2 cells and in mouse small intestine during the perinatal period, The International Journal of Biochemistry & Cell Biology 42 (2010) 1363–1369, https://doi.org/10.1016/j.biocel.2009.07.019. Crossref, Google Scholar
95. N. Hubert and M. W. Hentze, Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function, Proceedings of the National Academy of Sciences of the United States of America 99 (2002) 12345–12350, https://doi.org/10.1073/pnas.192423399. Crossref, Google Scholar
96. D. Tchernitchko, M. Bourgeois, M. E. Martin and C. Beaumont, Expression of the two mRNA isoforms of the iron transporter Nramp2/DMTI in mice and function of the iron responsive element, Biochemical Journal 363 (2002) 449–455. Crossref, Google Scholar
97. I. Andolfo et al., Regulation of divalent metal transporter 1 (DMT1) non-IRE isoform by the microRNA Let-7d in erythroid cells, Haematologica 95 (2010) 1244–1252, https://doi.org/10.3324/haematol.2009.020685. Crossref, Google Scholar
98. S. Jiang et al., Identification and functional verification of microRNA-16 family targeting intestinal divalent metal transporter 1 (DMT1) in vitro and in vivo, Frontiers in Physiology 10 (2019) 819, https://doi.org/10.3389/fphys.2019.00819. Crossref, Google Scholar
99. F. M. Torti and S. V. Torti, Regulation of ferritin genes and protein, Blood 99 (2002) 3505–3516. Crossref, Google Scholar
100. U. Carmona, L. Li, L. Zhang and M. Knez, Ferritin light-chain subunits: Key elements for the electron transfer across the protein cage, Chemical Communications 50 (2014) 15358–15361, https://doi.org/10.1039/c4cc07996e. Crossref, Google Scholar
101. S. I. Shpyleva et al., Role of ferritin alterations in human breast cancer cells, Breast Cancer Research and Treatment 126 (2011) 63–71, https://doi.org/10.1007/s10549-010-0849-4. Crossref, Google Scholar
102. X. Yang et al., miR-200b regulates epithelial-mesenchymal transition of chemo-resistant breast cancer cells by targeting FN1, Discovery Medicine 24 (2017) 75–85. Google Scholar
103. J. J. Chan et al., A FTH1 gene: Pseudogene:MicroRNA network regulates tumorigenesis in prostate cancer, Nucleic Acids Research 46 (2018) 1998–2011, https://doi.org/10.1093/nar/gkx1248. Crossref, Google Scholar
104. K. R. Babu and M. U. Muckenthaler, miR-20a regulates expression of the iron exporter ferroportin in lung cancer, Journal of Molecular Medicine 94 (2016) 347–359, https://doi.org/10.1007/s00109-015-1362-3. Crossref, Google Scholar
105. S. Jiang et al., MiR-20b down-regulates intestinal ferroportin expression in vitro and in vivo, Cells 8 (2019) https://doi.org/10.3390/cells8101135. Crossref, Google Scholar
106. Y. Kong et al., Ferroportin downregulation promotes cell proliferation by modulating the Nrf2-miR-17-5p axis in multiple myeloma, Cell Death & Disease 10 (2019) 624, https://doi.org/10.1038/s41419-019-1854-0. Crossref, Google Scholar
107. C. Sangokoya, J. F. Doss and J. T. Chi, Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin, PLOS Genetics 9 (2013) e1003408, https://doi.org/10.1371/journal.pgen.1003408. Crossref, Google Scholar
108. H. Kawabata et al., Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells, Blood 98 (2001) 2714–2719. Crossref, Google Scholar
109. R. E. Fleming et al., Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis, Proceedings of the National Academy of Sciences of the United States of America 97 (2000) 2214–2219, https://doi.org/10.1073/pnas.040548097. Crossref, Google Scholar
110. M. B. Johnson, J. Chen, N. Murchison, F. A. Green and C. A. Enns, Transferrin receptor 2: Evidence for ligand-induced stabilization and redirection to a recycling pathway, Molecular Biology of the Cell 18 (2007) 743–754, https://doi.org/10.1091/mbc.e06-09-0798. Crossref, Google Scholar
111. A. B. Core, S. Canali and J. L. Babitt, Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis, Frontiers in Pharmacology 5 (2014) 104, https://doi.org/10.3389/fphar.2014.00104. Crossref, Google Scholar
112. M. Rausa et al., Bmp6 expression in murine liver non parenchymal cells: A mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PLOS ONE 10 (2015) e0122696, https://doi.org/10.1371/journal.pone.0122696. Crossref, Google Scholar
113. A. U. Steinbicker et al., Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice, Blood 118 (2011) 4224–4230, https://doi.org/10.1182/blood-2011-03-339952. Crossref, Google Scholar
114. C. Mayeur, P. A. Leyton, S. A. Kolodziej, B. Yu and K. D. Bloch, BMP type II receptors have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism, Blood 124 (2014) 2116–2123, https://doi.org/10.1182/blood-2014-04-572644. Crossref, Google Scholar
115. R. H. Wang et al., A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression, Cell Metabolism 2 (2005) 399–409, https://doi.org/10.1016/j.cmet.2005.10.010. Crossref, Google Scholar
116. F. D’Alessio, M. W. Hentze and M. U. Muckenthaler, The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation, Journal of Hepatology 57 (2012) 1052–1060, https://doi.org/10.1016/j.jhep.2012.06.015. Crossref, Google Scholar
117. M. Castoldi et al., The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice, The Journal of Clinical Investigation 121 (2011) 1386–1396, https://doi.org/10.1172/JCI44883. Crossref, Google Scholar
118. C. Coulouarn, V. M. Factor, J. B. Andersen, M. E. Durkin and S. S. Thorgeirsson, Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties, Oncogene 28 (2009) 3526–3536, https://doi.org/10.1038/onc.2009.211. Crossref, Google Scholar
119. R. Asci et al., Trasferrin receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP( $+$ ) as Parkinson’s disease cellular model, Neuroscience Research 77 (2013) 121–127, https://doi.org/10.1016/j.neures.2013.09.003. Crossref, Google Scholar
120. Y. Fu et al., MiR-221 promotes hepatocellular carcinoma cells migration via targeting PHF2, BioMed Research International 2019 (2019) 4371405, https://doi.org/10.1155/2019/4371405. Crossref, Google Scholar
121. K. Iwai et al., Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: Implications for degradation of oxidized proteins, Proceedings of the National Academy of Sciences of the United States of America 95 (1998) 4924–4928. Crossref, Google Scholar
122. R. Ripa et al., MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging, BMC Biology 15 (2017) 9, https://doi.org/10.1186/s12915-017-0354-x. Crossref, Google Scholar
123. J. J. Kwon, T. D. Factora, S. Dey and J. Kota, A systematic review of miR-29 in cancer, Molecular Therapy Oncolytics 12 (2019) 173–194, https://doi.org/10.1016/j.omto.2018.12.011. Crossref, Google Scholar
124. M. L. Wallander, E. A. Leibold and R. S. Eisenstein, Molecular control of vertebrate iron homeostasis by iron regulatory proteins, Biochimica et Biophysica Acta 1763 (2006) 668–689, https://doi.org/10.1016/j.bbamcr.2006.05.004. Crossref, Google Scholar
125. S. Y. Chan et al., MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2, Cell Metabolism 10 (2009) 273–284, https://doi.org/10.1016/j.cmet.2009.08.015. Crossref, Google Scholar