microRNAs modulation by Carica papaya extracts in the K562 human cell line
DOI:
https://doi.org/10.25758/set.959Keywords:
β-hemoglobinopathies, Carica papaya, miRNAs, Fetal hemoglobinAbstract
Introduction – Hemoglobinopathies constitute one of the most prevalent groups of monogenic diseases worldwide. Currently, one of the available treatments consists of the pharmacological induction of fetal hemoglobin (HbF) using various chemical compounds, the most common one being hydroxyurea (HU). However, its high cost in developing countries and its poor safety profile limit its use. Therefore, it is essential to discover new HbF-inducing compounds with fewer side effects and that are easily accessible, such as natural compounds (e.g., Carica papaya L. leaf extract). Objective – To evaluate the effect of K562 cells’ (an immortalized human myeloid leukemia cell line) exposure to methanolic extracts of Carica papaya L. leaves (EMFCP) on the expression of miRNAs involved in HbF regulation. Methods – K562 cells were exposed for 24 hours to EMFCP (0.5, 50, and 100μg/mL) and HU (25μg/mL). The expression of miRNAs involved in HbF regulation (miR-486-3p, miR-34a-5p, miR-210-5p, miR-32-5p, and miR-96-5p) was analyzed by RT-qPCR, using miR-426-3p as an endogenous reference. Results – Data analysis demonstrated that EMFCP modulates miRNA expression levels, as confirmed by the observation of decreased expression levels of miR-486-3p, miR-34a-5p, miR-210-5p, miR-32-5p, and miR-96-5p, which are HbF regulators. Conclusion – This study suggests that EMFCP has the potential to induce HbF expression through the modulation of regulatory miRNAs, thus constituting a potentially effective approach in the treatment of β-hemoglobinopathies.
Downloads
References
Verma HK, Lakkakula S, Lakkakula BV. Retrospection of the effect of hydroxyurea treatment in patients with sickle cell disease. Acta Haematol Pol. 2018;49(1):1-8.
Gameiro MS. Caraterização molecular e funcional de variantes alfa de hemoglobina identificadas no Centro Hospitalar e Universitário de Coimbra [dissertation]. Coimbra: Faculdade de Ciências e Tecnologia da Universidade de Coimbra; 2012. Available from: https://hdl.handle.net/10316/25415
Starlard-Davenport A, Fitzgerald A, Pace BS. Exploring epigenetic and microRNA approaches for γ-globin gene regulation. Exp Biol Med. 2021;246(22):2347-57.
Tanhehco YC. Gene therapy for hemoglobinopathies. Transfus Apher Sci. 2021;60(1):103061.
Paikari A, Sheehan VA. Fetal haemoglobin induction in sickle cell disease. Br J Haematol. 2018;180(2):189-200.
Elendu C, Amaechi DC, Alakwe-Ojimba CE, Elendu TC, Elendu RC, Ayabazu CP, et al. Understanding sickle cell disease: causes, symptoms, and treatment options. Medicine (Baltimore). 2023;102(38):e35237.
Kukreja A, Wadhwa N, Tiwari A. Therapeutic role of natural agents in beta-thalassemia: a review. J Pharm Res. 2013;6(9):954-9.
Vuong QV, Hirun S, Roach PD, Bowyer MC, Phillips PA, Scarlett CJ. Effect of extraction conditions on total phenolic compounds and antioxidant activities of Carica papaya leaf aqueous extracts. J Herb Med. 2013;3(3):104-11.
Nugroho A, Heryani H, Choi JS, Park HJ. Identification and quantification of flavonoids in Carica papaya leaf and peroxynitrite-scavenging activity. Asian Pac J Trop Biomed. 2017;7(3):208-13.
Vij T, Prashar Y. A review on medicinal properties of Carica papaya Linn. Asian Pac J Trop Dis. 2015;5(1):1-6.
Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011;117(15):3945-53.
Tayebi B, Abrishami F, Alizadeh S, Minayi N, Mohammadian M, Soleimani M, et al. Modulation of microRNAs expression in hematopoietic stem cells treated with sodium butyrate in inducing fetal hemoglobin expression. Artif Cells Nanomed Biotechnol. 2017;45(1):146-56.
Saki N, Abroun S, Soleimani M, Kavianpour M, Shahjahani M, Mohammadi-Asl J, 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.
Bianchi N, Zuccato C, Finotti A, Lampronti I, Borgatti M, Gambari R. Involvement of miRNA in erythroid differentiation. Epigenomics. 2012;4(1):51-65.
Ribeiro E, Delgadinho M, Matos E, Santos R, Sousa D, Galante H, et al. Epigenetic and transcriptional modulator potential of epigallocatechin-3-gallate and genistein on fetal hemoglobin reactivators genes. Clin Complement Med Pharmacol. 2022;2(2):100034.
Li J, Lai Y, Shi L. BCL11A down-regulation induces γ-globin in human β-thalassemia major erythroid cells. Hemoglobin. 2018;42(4):225-30.
Cyrus C. The role of miRNAs as therapeutic tools in sickle cell disease. Medicina (Kaunas). 2021;57(10):1106.
Lulli V, Romania P, Morsilli O, Cianciulli P, Gabbianelli M, Testa U, et al. MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A. PLoS One. 2013;8(4):e60436.
Penglong T, Saensuwanna A, Kocharoenwat J, Boorintaragot W, Fupongsiriphan S, Srinoun K. MiR-144 regulates hemoglobin expression in human erythroid cell line. Walailak J Sci Technol. 2020;17(11):1221-9.
Zhang L, Liao Y, Tang L. MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. J Exp Clin Cancer Res. 2019;38(1):53.
Ward CM, Li B, Pace BS. Original research: stable expression of miR-34a mediates fetal hemoglobin induction in K562 cells. Exp Biol Med. 2016;241(7):719-29.
Sun KT, Huang YN, Palanisamy K, Chang SS, Wang IK, Wu KH, et al. Reciprocal regulation of γ-globin expression by exo-miRNAs: relevance to γ-globin silencing in β-thalassemia major. Sci Rep. 2017;7(1):202.
Kargutkar N, Sawant-Mulay M, Hariharan P, Chandrakala S, Nadkarni A. Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients. Sci Rep. 2023;13(1):369.
Yuan P, Tang C, Chen B, Lei P, Song J, Xin G, et al. miR‑32‑5p suppresses the proliferation and migration of pancreatic adenocarcinoma cells by targeting TLDC1. Mol Med Rep. 2021;24(5):752.
MicroRNA-Target Interactions. miRTarBase [Internet]. Available from: https://ngdc.cncb.ac.cn/databasecommons/database/id/167
TargetScanHuman. Human | miR-96-5p/1271-5p [homepage]. Whitehead Institute for Biomedical Research; 2021 Sep. Available from: https://www.targetscan.org/cgi-bin/targetscan/vert_80/targetscan.cgi?species=Human&gid=&mir_sc=&mir_c=&mir_nc=&mir_vnc=&mirg=miR-96-5p
Eltaweel NH, ElKamah GY, Khairat R, Atia HA, Amr KS. Epigenetic effects toward new insights as potential therapeutic target in B-thalassemia. J Genet Eng Biotechnol. 2021;19(1):51.
Chou YC, Chen RL, Lai ZS, Song JS, Chao YS, Shen CK. Pharmacological induction of human fetal globin gene in hydroxyurea-resistant primary adult erythroid cells. Mol Cell Biol. 2015;35(14):2541-53.
Jha N, Mangukia N, Gadhavi H, Patel M, Bhavsar M, Rawal R, et al. Small RNA sequencing and identification of papaya (Carica papaya L.) miRNAs with potential cross-kingdom human gene targets. Mol Genet Genomics. 2022;297(4):981-97.
De Montalembert M, Voskaridou E, Oevermann L, Cannas G, Habibi A, Loko G, et al. Real-life experience with hydroxyurea in patients with sickle cell disease: results from the prospective ESCORT-HU cohort study. Am J Hematol. 2021;96(10):1223-31.
Sharma A, Sharma R, Sharma M, Kumar M, Barbhai MD, Lorenzo JM, et al. Carica papaya L. leaves: deciphering its antioxidant bioactives, biological activities, innovative products, and safety aspects. Oxid Med Cell Longev. 2022;2022:2451733.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Saúde & Tecnologia

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The journal Saúde & Tecnologia offers immediate free access to its content, following the principle that making scientific knowledge available to the public free of charge provides greater worldwide democratization of knowledge.
The journal Saúde & Tecnologia does not charge authors any submission or article processing charges (APC).
All content is licensed under a Creative Commons CC-BY-NC-ND license. Authors have the right to: reproduce their work in physical or digital form for personal, professional, or teaching use, but not for commercial use (including the sale of the right to access the article); deposit on their website, that of their institution or in a repository an exact copy in electronic format of the article published by Saúde & Tecnologia, provided that reference is made to its publication in Saúde & Tecnologia and its content (including symbols identifying the journal) is not altered; publish in a book of which they are authors or editors the total or partial content of the manuscript, provided that reference is made to its publication in Saúde & Tecnologia.
