Dysregulated Expression of miR-222 and miR-15a in Transfusion-Dependent Thalassemia: Associations with Torque Teno Virus and Cytomegalovirus Infections
-
Mahdiyar Iravani Saadi
,
Nasrin Noshadi
,
Fakhroddin Hosseini
,
Soodabeh Zare
,
Ramin Yaghoobi
,
Zahed Karimi
,
Zahra Ghahramani
,
Mani Ramzi
Abstract
Background: Beta-thalassemia is a hereditary blood disorder characterized by reduced synthesis of the beta-globin chain. MicroRNAs (miRs) are small RNA molecules that regulate gene expression and have been implicated in beta-thalassemia. To explore dysregulated miR-222 and miR-15a expression in transfusion-dependent beta-thalassemia and assess their potential associations with Torque Teno Virus and cytomegalovirus infections.
Materials and Methods: This study included 57 TDT patients registered at the Thalassemia Clinic affiliated with the Hematology Research Center, Shiraz, Iran. The expression levels of miR-222 and miR-15a were analyzed using the real-time SYBR Green PCR method. TTV and CMV infections were detected by analyzing the presence of their genomic DNA using an in-house semi-nested PCR protocol.
Results: The expression level of miR-222 was significantly up-regulated (47.5-fold, P≤0.001) in TDT patients compared to healthy controls. However, the expression of miR-15a in TDT patients was slightly decreased compared to healthy controls, but the difference was not statistically significant (P=0.193). TTV infection was observed in 21.1% of TDT patients, while CMV infection was detected in 5.2% of the patients. Although miR-222 and miR-15a gene expression levels were higher in TTV-positive patients compared to TTV-negative patients, the differences were not statistically significant (P=0.926 and P=0.243, respectively).
Conclusion: MiR-222 was up-regulated in TDT patients, but miR-15a did not show a significant difference. TTV and CMV infections were detected, but their association with miR expression was not significant, possibly due to the small sample size. Larger studies are needed for a more comprehensive evaluation.
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6. Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83-6.
7. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834-8.
8. Galehdari H, Azarshin SZ, Bijanzadeh M, et al. Polymorphism studies on microRNA targetome of thalassemia. Bioinformation. 2018;14(5):252-258.
9. Ferreira RA. Análise do perfil de expressão de fatores de transcrição e miRNAs em reticulócitos de pacientes com talassemia beta intermediária e anemia falciforme.2010;
10. Felli N, Fontana L, Pelosi E, et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18081-6.
11. Azzouzi I, Moest H, Winkler J. et al. MicroRNA-96 directly inhibits γ-globin expression in human erythropoiesis.PloS One. 2011;6(7):e22838.
12. Gabbianelli M, Testa U, Morsilli O, et al.Mechanism of human Hb switching: a possible role of the kit receptor/miR 221-222 complex. Haematologica. 2010;95(8):1253-60.
13. Saki N, Abroun S, Soleimani M, et al. MicroRNA expression in β-thalassemia and sickle cell disease: a role in the induction of fetal hemoglobin.Cell J. 2016;17(4):583-92.
14. Lee JY, Kim M, Heo HR, et al. Inhibition of microRNA-221 and 222 enhances hematopoietic differentiation from human pluripotent stem cells via c-KIT upregulation. Mol Cells. 2018;41(11):971-978.
15. Wang D, Sang Y, Sun T, et al. Emerging roles and mechanisms of microRNA‑222‑3p in human cancer (Review).Int J Oncol. 2021;58(5):20.
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28. Saadi MI, Hosseini F, Rostamipour HA, et al. Investigating Apoptotic Effect through Blocking miR-181b and miR-222 Using LNA-anti-miRNA in HL-60 Cell Line: Strategies to Improve Hematopoietic Stem Cell Transplantation. Int J Organ Transplant Med. 2024;15(1):26-37.
29. Torkamani M, Forghanifard MM, Zarrinpour V, et al. Investigating the Impact of LNA-anti-miR-92b, miR-181b, TNF-α, and Piperine on Gene Expression and Cell Viability in Jurkat Cells: Implications for Acute Lymphoblastic Leukemia. GMJ. 2025;14:e3566.
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31. Kazemi MJ, Yaghobi R, Iravani Saadi M, et al. Association Between TT Virus Infection and Cirrhosis in Liver Transplant Patients. Hepat Mon. 2015;15(9):e28370.
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35. Brück T. Biotechnology & Biomedical Engineering. Biotechnol Bioeng .2014;2(1):1033
36. Yavarian M, Karimi M, Bakker E, et al. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89(10):1172-8.
37. Meloni A, Pistoia L, Spasiano A, et al. Oxidative stress and antioxidant status in adult patients with transfusion-dependent thalassemia: Correlation with demographic, laboratory, and clinical biomarkers. Antioxidants(Basel) 2024;13(4):446
38. Saito Y, Liang G, Egger G, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006;9(6):435-43.
39. Saito Y, Jones PM. Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle. 2006;5(19):2220-2.
40. Murakami Y, Toyoda H, Tanaka M, et al. The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families.PloS One. 2011;6(1):e16081.
41. Peta E, Sinigaglia A, Masi G, et al. HPV16 E6 and E7 upregulate the histone lysine demethylase KDM2B through the c-MYC/miR-146a-5p axys. Oncogene. 2018;37(12):1654-1668.
42. Swaminathan S, Murray DD, Kelleher AD. The role of microRNAs in HIV-1 pathogenesis and therapy.AIDS. 2012;26(11):1325-34.
43. Toropko M, Chuvpilo S, Karabelsky A. MiRNA-Mediated Mechanisms in the Generation of Effective and Safe Oncolytic Viruses.Pharmaceutics. 2024;16(8):986.
44. Zhao H, Kalota A, Jin S, et al. The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells. Blood. 2009;113(3):505-16.
45. Liu Z, Cheng C, Luo X et al. Retracted article: CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma.BMC Cancer. 2016;16:238.
46. Turco C, Donzelli S, Fontemaggi G. miR-15/107 microRNA gene group: characteristics and functional implications in cancer. Front Cell and Dev Biol. 2020;8:427.
47. Krol J, Loedige I, Filipowicz W.The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597-610.
48. Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 2010:79:321-49.
49. Hao M, Zhang L, An G, et al. Suppressing miRNA-15a/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells. J Hematol Oncol. 2011;4:37.
50. Liu LF, Liang Z, Lv ZR, et al. MicroRNA-15a/b are up-regulated in response to myocardial ischemia/reperfusion injury. J Geriatr Cardiol. 2012;9(1):28-32.
51. O'Connell RM, Taganov KD, Boldin MP, et al. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104(5):1604-9.
52. Lulli V, Romania P, Morsilli O, et al. MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A. PloS One. 2013;8(4):e60436.
53. Sangokoya C, Telen MJ, Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood. 2010;116(20):4338-4348.
54. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102(39):13944-9.
55. Cyrus C.The role of miRNAs as therapeutic tools in sickle cell disease. Medicina (Kaunas). 2021;57(10):1106.
56. Mollah AH, Nahar N, Siddique MA, et al. Common transfusion-transmitted infectious agents among thalassaemic children in Bangladesh. J Health Popul Nutr. 2003;21(1):67-71.
57. Ismail M: CMV Infection Among Pregnant Women: Seroprevalence and The Major Risk Factors Predisposing to Cytomegalovirus Infection: LAP LAMBERT Academic Publishing; 2014.
58. Safabakhsh H, Tehranian F, Tehranian B, et al. Prevalence of anti-CMV antibodies in blood donors in Mashhad, Iran. Iran J Epidemiol. 2013;9(1):52-57.
59. Moghimi M, Doosti M, Vahedian-Ardakani H, et al. Serological Study on Cytomegalovirus and Toxoplasma Gondii in Thalassemia Major Patients of Yazd, Iran. Iran J Ped Hematol Oncol. 2015;5(3):149-154.
60. Choobineh H, Alizadeh S, Yazdi MS, et al. Serological Evaluation of Major Beta Thalassemia Patients below15 for Cytomegalovirus Infection in Iran. Res J Biol Sci. 2009;2:584-589.
61. Aghaeipour M, Tarabadi F, Shaeigan M, et al. Detection of serologic prevalence of anti-CMV antibodies in thalassemia major patients and blood donors. Blood J. 2005;1(2):37-41.
62. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155-167.
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2. Mathias LA, Fisher TC, Zeng L et al. Ineffective erythropoiesis in β-thalassemia major is due to apoptosis at the polychromatophilic normoblast stage. Expe Hematol. 2000;28(12):1343-53.
3. Buccisano F, Maurillo L, Spagnoli A et al. Monitoring of minimal residual disease in acute myeloid leukemia. Curr Opin Oncol. 2009; 21(6):582-8.
4. Garzon R, Marcucci G. Potential of microRNAs for cancer diagnostics, prognostication and therapy. Curr Opin Oncol. 2012;24(6):655-9.
5. Marcucci G, Radmacher MD, Mrozek K, et al. MicroRNA expression in acute myeloid leukemia.Curr Hematol Malig Rep. 2009;4(2):83-8.
6. Chen CZ, Li L, Lodish HF, et al. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83-6.
7. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834-8.
8. Galehdari H, Azarshin SZ, Bijanzadeh M, et al. Polymorphism studies on microRNA targetome of thalassemia. Bioinformation. 2018;14(5):252-258.
9. Ferreira RA. Análise do perfil de expressão de fatores de transcrição e miRNAs em reticulócitos de pacientes com talassemia beta intermediária e anemia falciforme.2010;
10. Felli N, Fontana L, Pelosi E, et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18081-6.
11. Azzouzi I, Moest H, Winkler J. et al. MicroRNA-96 directly inhibits γ-globin expression in human erythropoiesis.PloS One. 2011;6(7):e22838.
12. Gabbianelli M, Testa U, Morsilli O, et al.Mechanism of human Hb switching: a possible role of the kit receptor/miR 221-222 complex. Haematologica. 2010;95(8):1253-60.
13. Saki N, Abroun S, Soleimani M, et al. MicroRNA expression in β-thalassemia and sickle cell disease: a role in the induction of fetal hemoglobin.Cell J. 2016;17(4):583-92.
14. Lee JY, Kim M, Heo HR, et al. Inhibition of microRNA-221 and 222 enhances hematopoietic differentiation from human pluripotent stem cells via c-KIT upregulation. Mol Cells. 2018;41(11):971-978.
15. Wang D, Sang Y, Sun T, et al. Emerging roles and mechanisms of microRNA‑222‑3p in human cancer (Review).Int J Oncol. 2021;58(5):20.
16. Nassiri SM, Ahmadi Afshar N, Almasi P. Insight into microRNAs' involvement in hematopoiesis: current standing point of findings. Stem Cell Res Ther. 2023;14(1):282.
17. Wang H, Chen M, Xu S, et al. Abnormal regulation of microRNAs and related genes in pediatric β-thalassemia. J Clin Lab Anal. 2021;35(9):e23945.
18. Wang F, Ling L, Yu D. MicroRNAs in β-thalassemia. Am J Med Sci. 2021;362(1):5-12.
19. Bouzari M, Baygloo NS. Detection of torque teno virus (TTV) in domestic village chickens in Iran. Vet Res Forum. 2013;4(1):55-8.
20. Hafez MM, Shaarawy SM, Hassan AA, et al. Prevalence of transfusion transmitted virus (TTV) genotypes among HCC patients in Qaluobia governorate. Virol J. 2007;4:135.
21. Mansouritorghabeh H, Badiei Z. Transfusion-transmitted viruses in individuals with β thalassemia major at Northeastern Iran, a retrospective sero-epidemiological survey. Iran J Blood Cancer. 2008;1(1):1-4.
22. Abdalla N, Galal A, Fatouh A, et al. Transfusion transmitted virus (TTV) infection in polytransfused Egyptian thalassemic children. J Med Sci. 2006;6(5):833-837.
23. Nyholm JL, Schleiss MR. Prevention of maternal cytomegalovirus infection: current status and future prospects. Int J Womens Health. 2010:2:23-35.
24. Najim OA, Hassan MK. Prevalence of hepatitis C virus seropositivity among multitransfused patients with hereditary anemias in Basra, Iraq. Iraqi J Hematol. 2018;7(1):39-44.
25. Kattamis A, Forni GL, Aydinok Y, et al. Changing patterns in the epidemiology of β-thalassemia. Eur J Haematol. 2020;105(6):692-703.
26. Hou W, Gibbs JS, Lu X, et al. Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells. Blood. 2012;119(13):3128-31.
27. Ramzi M, Rostamipour HA, Iravani Saadi M, et al. MiR-155 and MiR-1275 relation with graft-versus-host disease and hepatitis B in hematopoietic stem cell transplant recipients.Virusdisease. 2025;36(2):326-334.
28. Saadi MI, Hosseini F, Rostamipour HA, et al. Investigating Apoptotic Effect through Blocking miR-181b and miR-222 Using LNA-anti-miRNA in HL-60 Cell Line: Strategies to Improve Hematopoietic Stem Cell Transplantation. Int J Organ Transplant Med. 2024;15(1):26-37.
29. Torkamani M, Forghanifard MM, Zarrinpour V, et al. Investigating the Impact of LNA-anti-miR-92b, miR-181b, TNF-α, and Piperine on Gene Expression and Cell Viability in Jurkat Cells: Implications for Acute Lymphoblastic Leukemia. GMJ. 2025;14:e3566.
30. Ramzi M, Iravani Saadi M, Zarei T, et al. Association Between Cytotoxic T-Lymphocyte Antigen 4 Gene Polymorphisms and Torque Teno Virus Infection After Hematopoietic Stem Cell Transplantation. Experimental and clinical transplantation. Exp Clin Transplant. 2021;19(3):259-263.
31. Kazemi MJ, Yaghobi R, Iravani Saadi M, et al. Association Between TT Virus Infection and Cirrhosis in Liver Transplant Patients. Hepat Mon. 2015;15(9):e28370.
32. Kanaan A, Cour I, Alvarez-Lafuente R et al. Significance of nested PCR and quantitative real time PCR for cytomegalovirus detection in renal transplant recipients.Int J Antimicrob Agents. 2004;24(5):455-462.
33. Rujito L, Wardana T, Mulyanto J, et al. Profiling circulating microRNA and regulatory pathways in transfusion-dependent thalassemia and thalassemia trait compared to healthy controls: a preliminary study.ExRNA 2024;6(3):1-17.
34. Levin C, Koren A, Rebibo-Sabbah A, et al. Extracellular vesicle microRNA that are involved in β-thalassemia complications. Int J Mol Sci. 2021;22(18):9760.
35. Brück T. Biotechnology & Biomedical Engineering. Biotechnol Bioeng .2014;2(1):1033
36. Yavarian M, Karimi M, Bakker E, et al. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89(10):1172-8.
37. Meloni A, Pistoia L, Spasiano A, et al. Oxidative stress and antioxidant status in adult patients with transfusion-dependent thalassemia: Correlation with demographic, laboratory, and clinical biomarkers. Antioxidants(Basel) 2024;13(4):446
38. Saito Y, Liang G, Egger G, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006;9(6):435-43.
39. Saito Y, Jones PM. Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle. 2006;5(19):2220-2.
40. Murakami Y, Toyoda H, Tanaka M, et al. The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families.PloS One. 2011;6(1):e16081.
41. Peta E, Sinigaglia A, Masi G, et al. HPV16 E6 and E7 upregulate the histone lysine demethylase KDM2B through the c-MYC/miR-146a-5p axys. Oncogene. 2018;37(12):1654-1668.
42. Swaminathan S, Murray DD, Kelleher AD. The role of microRNAs in HIV-1 pathogenesis and therapy.AIDS. 2012;26(11):1325-34.
43. Toropko M, Chuvpilo S, Karabelsky A. MiRNA-Mediated Mechanisms in the Generation of Effective and Safe Oncolytic Viruses.Pharmaceutics. 2024;16(8):986.
44. Zhao H, Kalota A, Jin S, et al. The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells. Blood. 2009;113(3):505-16.
45. Liu Z, Cheng C, Luo X et al. Retracted article: CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma.BMC Cancer. 2016;16:238.
46. Turco C, Donzelli S, Fontemaggi G. miR-15/107 microRNA gene group: characteristics and functional implications in cancer. Front Cell and Dev Biol. 2020;8:427.
47. Krol J, Loedige I, Filipowicz W.The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597-610.
48. Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 2010:79:321-49.
49. Hao M, Zhang L, An G, et al. Suppressing miRNA-15a/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells. J Hematol Oncol. 2011;4:37.
50. Liu LF, Liang Z, Lv ZR, et al. MicroRNA-15a/b are up-regulated in response to myocardial ischemia/reperfusion injury. J Geriatr Cardiol. 2012;9(1):28-32.
51. O'Connell RM, Taganov KD, Boldin MP, et al. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104(5):1604-9.
52. Lulli V, Romania P, Morsilli O, et al. MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A. PloS One. 2013;8(4):e60436.
53. Sangokoya C, Telen MJ, Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood. 2010;116(20):4338-4348.
54. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102(39):13944-9.
55. Cyrus C.The role of miRNAs as therapeutic tools in sickle cell disease. Medicina (Kaunas). 2021;57(10):1106.
56. Mollah AH, Nahar N, Siddique MA, et al. Common transfusion-transmitted infectious agents among thalassaemic children in Bangladesh. J Health Popul Nutr. 2003;21(1):67-71.
57. Ismail M: CMV Infection Among Pregnant Women: Seroprevalence and The Major Risk Factors Predisposing to Cytomegalovirus Infection: LAP LAMBERT Academic Publishing; 2014.
58. Safabakhsh H, Tehranian F, Tehranian B, et al. Prevalence of anti-CMV antibodies in blood donors in Mashhad, Iran. Iran J Epidemiol. 2013;9(1):52-57.
59. Moghimi M, Doosti M, Vahedian-Ardakani H, et al. Serological Study on Cytomegalovirus and Toxoplasma Gondii in Thalassemia Major Patients of Yazd, Iran. Iran J Ped Hematol Oncol. 2015;5(3):149-154.
60. Choobineh H, Alizadeh S, Yazdi MS, et al. Serological Evaluation of Major Beta Thalassemia Patients below15 for Cytomegalovirus Infection in Iran. Res J Biol Sci. 2009;2:584-589.
61. Aghaeipour M, Tarabadi F, Shaeigan M, et al. Detection of serologic prevalence of anti-CMV antibodies in thalassemia major patients and blood donors. Blood J. 2005;1(2):37-41.
62. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155-167.
63. Cortez MA, Bueso-Ramos C, Ferdin J, et al. MicroRNAs in body fluids—the mix of hormones and biomarkers. Nature Rev Clin Oncol. 2011;8(8):467-477.
64. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.
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66. Toyoda H, Fukuda Y, Nakano I et al. TT virus genotype changes frequently in multiply transfused patients with hemophilia but rarely in patients with chronic hepatitis C and in healthy subjects. Transfusion. 2001;41(9):1130-5.
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| Files | ||
| Issue | Vol 19 No 4 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Transfusion-dependent beta-thalassemia; MicroRNA; Expression levels; Viral infection prevalence; miRNA | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Iravani Saadi M, Noshadi N, Hosseini F, Zare S, Yaghoobi R, Karimi Z, Ghahramani Z, Ramzi M. Dysregulated Expression of miR-222 and miR-15a in Transfusion-Dependent Thalassemia: Associations with Torque Teno Virus and Cytomegalovirus Infections. Int J Hematol Oncol Stem Cell Res. 2025;19(4):365-376.
