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Circulating miRNAs and tissue iron overload in transfusion-dependent β-thalassemia major: novel predictors and follow-up guide

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A Correction to this article was published on 06 October 2021

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Abstract

Tissue iron overload is a life-threatening scenario in children with transfusion-dependent β-thalassemia major, miRNAs that are involved in iron hemostasis could serve as therapeutic targets for control of iron overload. We aimed to find out the association between three iron-related miRNAs “miR-let-7d, miR-122, and miR-200b” and excess iron in tissues, in transfusion-dependent β-thalassemia major patients. Circulating miRNA expressions are measured in peripheral blood (PB) samples using qPCR of transfusion-dependent (TDT) β-thalassemia patients (n = 140) and normalized to non-transfusion-dependent (NTDT) β-thalassemia (n = 45). Results revealed that plasma expression levels of miR-let-7d and miR-200b were significantly downregulated in TDT patients; however, miR-122 was upregulated. In terms of tissue iron load, aberrant expression of miRNAs was significantly associated with increased—iron accumulation in hepatic and cardiac tissues. We concluded that circulating miRNAs are strong candidates that associate iron hemostasis in transfusion-dependent β-thalassemia major patients. And by extension, targeting miR-let-7d, miR-122, and miR-200 might serve as novel sensitive, specific and non-invasive predictor biomarkers for cellular damage under condition of tissue iron excess.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable.

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References

  1. Alateeq S et al (2018) Identification of on-target mutagenesis during correction of a beta-thalassemia splice mutation in iPS cells with optimised CRISPR/Cas9-double nickase reveals potential safety concerns. APL Bioeng 2(4):046103

    PubMed  PubMed Central  Google Scholar 

  2. Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V (2014) Guidelines for the management of transfusion dependent thalassaemia (TDT), 3rd edn. Thalassaemia International Federation, Nicosia. https://pubmed.ncbi.nlm.nih.gov/25610943

  3. Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA (2013) Non-transfusion-dependent thalassemias, (in eng). Haematologica 98(6):833–844

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Taher AT, Saliba AN (2017) Iron overload in thalassemia: different organs at different rates, (in eng), Hematology. Am Soc Hematol Educ Program 2017(1):265–271

    Google Scholar 

  5. Zakaria M and Hassan T (2019) Oxidative stress and iron overload in β-thalassemia: An Overview, Beta Thalassemia, IntechOpen. https://doi.org/10.5772/intechopen.90492. https://www.intechopen.com/chapters/70487

  6. Chaichompoo P et al (2019) Abnormal red blood cell morphological changes in thalassaemia associated with iron overload and oxidative stress. J Clin Pathol 72:jclinpath-2019

    Google Scholar 

  7. De Sanctis V, Giovannini M (2011) Endocrine histology findings in a prepubertal thalassemic girl with multiple endocrine complications secondary to iron overload, (in eng). Georgian Med News 193:51–55

    Google Scholar 

  8. Bajoria R, Chatterjee R (2011) Hypogonadotrophic hypogonadism and diminished gonadal reserve accounts for dysfunctional gametogenesis in thalassaemia patients with iron overload presenting with infertility, (in eng). Hemoglobin 35(5–6):636–642

    CAS  PubMed  Google Scholar 

  9. Gattermann N, Rachmilewitz EA (2011) Iron overload in MDS-pathophysiology, diagnosis, and complications, (in eng). Ann Hematol 90(1):1–10

    CAS  PubMed  Google Scholar 

  10. Farmaki K, Tzoumari I, Pappa C (2011) Oral chelators in transfusion-dependent thalassemia major patients may prevent or reverse iron overload complications, (in eng). Blood Cells Mol Dis 47(1):33–40

    CAS  PubMed  Google Scholar 

  11. Liu Q, Sun L, Tan Y, Wang G, Lin X, Cai L (2009) Role of iron deficiency and overload in the pathogenesis of diabetes and diabetic complications, (in eng). Curr Med Chem 16(1):113–129

    CAS  PubMed  Google Scholar 

  12. Brittenham GM et al (1994) Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major, (in eng). N Engl J Med 331(9):567–573

    CAS  PubMed  Google Scholar 

  13. Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B (2000) Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major, (in eng). Br J Haematol 110(4):971–977

    CAS  PubMed  Google Scholar 

  14. Pinto VM, Forni GL (2020) Management of iron overload in beta-thalassemia patients: clinical practice update based on case series. Int J Mol Sci 21(22):8771. https://doi.org/10.3390/ijms21228771

    Article  CAS  PubMed Central  Google Scholar 

  15. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function, (in eng). Cell 116(2):281–297

    CAS  PubMed  Google Scholar 

  16. Miska EA (2005) How microRNAs control cell division, differentiation and death, (in eng). Curr Opin Genet Dev 15(5):563–568

    CAS  PubMed  Google Scholar 

  17. Lytle JR, Yario TA, Steitz JA (2007) Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5’ UTR as in the 3’ UTR, (in eng). Proc Natl Acad Sci USA 104(23):9667–9672

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ørom UA, Nielsen FC, Lund AH (2008) MicroRNA-10a binds the 5’UTR of ribosomal protein mRNAs and enhances their translation, (in eng). Mol Cell 30(4):460–471

    PubMed  Google Scholar 

  19. Greene CM, Varley RB, Lawless MW (2013) MicroRNAs and liver cancer associated with iron overload: therapeutic targets unravelled, (in eng). World J Gastroenterol 19(32):5212–5226

    PubMed  PubMed Central  Google Scholar 

  20. Chen Y, Gelfond JA, McManus LM, Shireman PK (2009) Reproducibility of quantitative RT-PCR array in miRNA expression profiling and comparison with microarray analysis, (in eng). BMC Genomics 10:407

    PubMed  PubMed Central  Google Scholar 

  21. Reid G, Kirschner MB, van Zandwijk N (2011) Circulating microRNAs: association with disease and potential use as biomarkers, (in eng). Crit Rev Oncol Hematol 80(2):193–208

    PubMed  Google Scholar 

  22. Mitchell PS et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection, (in eng). Proc Natl Acad Sci USA 105(30):10513–10518

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Masaki S, Ohtsuka R, Abe Y, Muta K, Umemura T (2007) Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis, (in eng). Biochem Biophys Res Commun 364(3):509–514

    CAS  PubMed  Google Scholar 

  24. Zhan M, Miller CP, Papayannopoulou T, Stamatoyannopoulos G, Song CZ (2007) MicroRNA expression dynamics during murine and human erythroid differentiation, (in eng). Exp Hematol 35(7):1015–1025

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Leecharoenkiat K et al (2017) Plasma microRNA-451 as a novel hemolytic marker for β0-thalassemia/HbE disease, (in eng). Mol Med Rep 15(5):2495–2502

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Sarakul O et al (2013) Enhanced erythroid cell differentiation in hypoxic condition is in part contributed by miR-210, (in eng). Blood Cells Mol Dis 51(2):98–103

    CAS  PubMed  Google Scholar 

  27. Castoldi M, Muckenthaler MU (2012) Regulation of iron homeostasis by microRNAs, (in eng). Cell Mol Life Sci 69(23):3945–3952

    CAS  PubMed  Google Scholar 

  28. Davis M, Clarke S (2013) Influence of microRNA on the maintenance of human iron metabolism, (in eng). Nutrients 5(7):2611–2628

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dykxhoorn DM et al (2009) miR-200 enhances mouse breast cancer cell colonization to form distant metastases, (in eng). PLoS One 4(9):e7181

    PubMed  PubMed Central  Google Scholar 

  30. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12(9):735–739

    CAS  PubMed  Google Scholar 

  31. Castoldi M et al (2011) The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice, (in eng). J Clin Invest 121(4):1386–1396

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hou W, Tian Q, Steuerwald NM, Schrum LW, Bonkovsky HL (2012) The let-7 microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates oxidant injury in human hepatocytes, (in eng). Biochim Biophys Acta 1819(11–12):1113–22

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen X et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases, (in eng). Cell Res 18(10):997–1006

    CAS  PubMed  Google Scholar 

  34. López P et al (2018) miR-155 and miR-122 expression of spermatozoa in obese subjects, (in eng). Front Genet 9:175–175

    PubMed  PubMed Central  Google Scholar 

  35. Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs, (in eng). Genome Res 19(1):92–105

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Yoshioka Y, Kosaka N, Ochiya T, Kato T (2012) Micromanaging iron homeostasis: hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins, (in eng). J Biol Chem 287(41):34110–34119

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schaar DG, Medina DJ, Moore DF, Strair RK, Ting Y (2009) miR-320 targets transferrin receptor 1 (CD71) and inhibits cell proliferation, (in eng). Exp Hematol 37(2):245–255

    CAS  PubMed  Google Scholar 

  38. Liao Y, Du X, Lönnerdal B (2010) miR-214 regulates lactoferrin expression and pro-apoptotic function in mammary epithelial cells, (in eng). J Nutr 140(9):1552–1556

    CAS  PubMed  Google Scholar 

  39. Liao Y, Lönnerdal B (2010) miR-584 mediates post-transcriptional expression of lactoferrin receptor in Caco-2 cells and in mouse small intestine during the perinatal period, (in eng). Int J Biochem Cell Biol 42(8):1363–1369

    CAS  PubMed  Google Scholar 

  40. Sangokoya C, Doss JF, Chi JT (2013) Iron-responsive miR-485–3p regulates cellular iron homeostasis by targeting ferroportin, (in eng). PLoS Genet 9(4):e1003408

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shpyleva SI et al (2011) Role of ferritin alterations in human breast cancer cells, (in eng). Breast Cancer Res Treat 126(1):63–71

    CAS  PubMed  Google Scholar 

  42. Ryu MS, Langkamp-Henken B, Chang SM, Shankar MN, Cousins RJ (2011) Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis, (in eng). Proc Natl Acad Sci USA 108(52):20970–20975

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hintze KJ, Katoh Y, Igarashi K, Theil EC (2007) Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1, (in eng). J Biol Chem 282(47):34365–34371

    CAS  PubMed  Google Scholar 

  44. Hou W, Tian Q, Zheng J, Bonkovsky HL (2010) MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins, (in eng). Hepatology 51(5):1494–1504

    CAS  PubMed  Google Scholar 

  45. Li Y et al (2012) Iron homeostasis regulates the activity of the microRNA pathway through poly(C)-binding protein 2. Cell Metab 15(6):895–904

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lis A, Paradkar PN, Singleton S, Kuo H-C, Garrick MD, Roth JA (2005) Hypoxia induces changes in expression of isoforms of the divalent metal transporter (DMT1) in rat pheochromocytoma (PC12) cells. Biochem Pharmacol 69(11):1647–1655

    CAS  PubMed  Google Scholar 

  47. Andolfo I et al (2010) Regulation of divalent metal transporter 1 (DMT1) non-IRE isoform by the microRNA Let-7d in erythroid cells, (in eng). Haematologica 95(8):1244–1252

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Arosio P, Levi S (2010) Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage, (in eng). Biochim Biophys Acta 1800(8):783–792

    CAS  PubMed  Google Scholar 

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The research is self-funded by the authors.

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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by SAM & HF. The first draft of the manuscript was written by NE and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Nashwa El-Khazragy.

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The study protocol number FMASU 28115/2017 was approved by the research ethics committee of the Faculty of Medicine, Ain Shams University. All participants were informed of the objectives of the study and signed informed-consent forms.

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The authors declare no competing interests.

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El-Khazragy, N., Matbouly, S., Hanna, D.H. et al. Circulating miRNAs and tissue iron overload in transfusion-dependent β-thalassemia major: novel predictors and follow-up guide. Ann Hematol 100, 2909–2917 (2021). https://doi.org/10.1007/s00277-021-04639-0

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