Abstract
Currently, acute graft-versus-host disease (aGVHD) diagnosis is based on clinical features and pathological findings. Until now, there is no non-invasive diagnostic test for aGVHD. MicroRNAs may act as promising predictive, diagnostic, or prognostic biomarkers for aGVHD. The purpose of the current study was to validate circulating microRNAs as diagnostic biomarkers to assist clinicians in promptly diagnosing aGVHD, so that treatment can be initiated earlier. In the present study, we evaluated six microRNAs (miR-455-3p, miR-5787, miR-6729-5p, miR-6776-5p, miR-548a-3p, and miR-6732-5p) selected from miRNA array data in 40 aGVHD patients compared to 40 non-GVHD patients with RT-qPCR. Target genes of differentially expressed microRNAs (DEMs) were predicted using Targetscan, miRanda, miRDB, miRWalk, PICTAR5, miRmap, DIANA, and miRTarBase algorithms, and their functions were analyzed using EnrichNet, Metascape, and DIANA-miRPath databases. The expressions of plasma miR-455-3p and miR-5787 were significantly downregulated, whereas miR-548a-3p was significantly upregulated in aGVHD patients compared to non-GVHD patients. Moreover, DEMs showed potentially high diagnostic accuracy for aGVHD. In silico analysis of DEMs provided valuable information on the role of DEMs in GVHD, immune regulation, and inflammatory response. Our study suggested that miR-455-3p, miR-5787, and miR-548a-3p could be used as potential noninvasive biomarkers in the diagnosis of aGVHD in addition to possible therapeutic targets in aGVHD.
Similar content being viewed by others
References
Shlomchik WD (2007) Graft-versus-host disease. Nat Rev Immunol 7(5):340–352. https://doi.org/10.1038/nri2000
Escamilla Gomez V, Garcia-Gutierrez V, Lopez Corral L, Garcia Cadenas I, Perez Martinez A, Marquez Malaver FJ, Caballero-Velazquez T, Gonzalez Sierra PA, Viguria Alegria MC, Parra Salinas IM, Calderon Cabrera C, Gonzalez Vicent M, Rodriguez Torres N, Parody Porras R, Ferra Coll C, Orti G, Valcarcel Ferreiras D, De la Camara LR, Moles P, Velazquez-Kennedy K, Joao Mende M, Caballero Barrigon D, Perez E, Martino Bofarull R, Saavedra Gerosa S, Sierra J, Poch M, Zudaire Ripa MT, Diaz Perez MA, Molina Angulo B, Sanchez Ortega I, Sanz Caballer J, Montoro Gomez J, Espigado Tocino I, Perez-Simon JA, Espanol G, de Trasplante H (2019) Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study. Bone Marrow Transplant.https://doi.org/10.1038/s41409-019-0731-x
Blazar BR, Murphy WJ, Abedi M (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12(6):443–458. https://doi.org/10.1038/nri3212
Motaei J, Yaghmaie M, Ahmadvand M, Pashaiefar H, Kerachian MA (2019) MicroRNAs as potential diagnostic, prognostic, and predictive biomarkers for acute graft-versus-host disease. Biol Blood Marrow Transplant.https://doi.org/10.1016/j.bbmt.2019.08.004
Crossland RE, Norden J, Juric MK, Green K, Pearce KF, Lendrem C, Greinix HT, Dickinson AM (2017) Expression of serum microRNAs is altered during acute graft-versus-host disease. Front Immunol 8:308. https://doi.org/10.3389/fimmu.2017.00308
Xiao B, Wang Y, Li W, Baker M, Guo J, Corbet K, Tsalik EL, Li QJ, Palmer SM, Woods CW, Li Z, Chao NJ, He YW (2013) Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease. Blood 122(19):3365–3375. https://doi.org/10.1182/blood-2013-06-510586
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. https://doi.org/10.1016/j.cell.2009.01.002
Leonhardt F, Grundmann S, Behe M, Bluhm F, Dumont RA, Braun F, Fani M, Riesner K, Prinz G, Hechinger AK, Gerlach UV, Dierbach H, Penack O, Schmitt-Graff A, Finke J, Weber WA, Zeiser R (2013) Inflammatory neovascularization during graft-versus-host disease is regulated by alphav integrin and miR-100. Blood 121(17):3307–3318. https://doi.org/10.1182/blood-2012-07-442665
Wang L, Romero M, Ratajczak P, Leboeuf C, Belhadj S, Peffault de Latour R, Zhao WL, Socie G, Janin A (2013) Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia. Bone Marrow Transplant 48(6):849–853. https://doi.org/10.1038/bmt.2012.237
Stickel N, Prinz G, Pfeifer D, Hasselblatt P, Schmitt-Graeff A, Follo M, Thimme R, Finke J, Duyster J, Salzer U, Zeiser R (2014) MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD. Blood 124(16):2586–2595. https://doi.org/10.1182/blood-2014-04-569046
Sang W, Zhang C, Zhang D, Wang Y, Sun C, Niu M, Sun X, Zhou C, Zeng L, Pan B, Chen W, Yan D, Zhu F, Wu Q, Cao J, Zhao K, Chen C, Li Z, Li D, Loughran TP Jr, Xu K (2015) MicroRNA-181a, a potential diagnosis marker, alleviates acute graft versus host disease by regulating IFN-gamma production. Am J Hematol 90(11):998–1007. https://doi.org/10.1002/ajh.24136
Sun Y, Oravecz-Wilson K, Mathewson N, Wang Y, McEachin R, Liu C, Toubai T, Wu J, Rossi C, Braun T, Saunders T, Reddy P (2015) Mature T cell responses are controlled by microRNA-142. J Clin Invest 125(7):2825–2840. https://doi.org/10.1172/JCI78753
Ranganathan P, Ngankeu A, Zitzer NC, Leoncini P, Yu X, Casadei L, Challagundla K, Reichenbach DK, Garman S, Ruppert AS, Volinia S, Hofstetter J, Efebera YA, Devine SM, Blazar BR, Fabbri M, Garzon R (2017) Serum miR-29a is upregulated in acute graft-versus-host disease and activates dendritic cells through TLR binding. J Immunol 198(6):2500–2512. https://doi.org/10.4049/jimmunol.1601778
Zitzer NC, Snyder K, Meng X, Taylor PA, Efebera YA, Devine SM, Blazar BR, Garzon R, Ranganathan P (2018) MicroRNA-155 modulates acute graft-versus-host disease by impacting T cell expansion, migration, and effector function. J Immunol 200(12):4170–4179. https://doi.org/10.4049/jimmunol.1701465
Gimondi S, Dugo M, Vendramin A, Bermema A, Biancon G, Cavané A, Corradini P, Carniti C (2016) Circulating miRNA panel for prediction of acute graft-versus-host disease in lymphoma patients undergoing matched unrelated hematopoietic stem cell transplantation. Exp Hematol 44(7):624-634.e621. https://doi.org/10.1016/j.exphem.2016.03.005
PrzepiorkaWeisdorf DD, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15(6):825–828
Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373(9674):1550–1561. https://doi.org/10.1016/S0140-6736(09)60237-3
Nassereddine S, Rafei H, Elbahesh E, Tabbara I (2017) Acute graft versus host disease: a comprehensive review. Anticancer Res 37(4):1547–1555. https://doi.org/10.21873/anticanres.11483
Ramachandran V, Kolli SS, Strowd LC (2019) Review of graft-versus-host disease. Dermatol Clin 37(4):569–582. https://doi.org/10.1016/j.det.2019.05.014
Carreras E, Carlo Dufour MM, Kröger N (2019) The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Springer, Cham.https://doi.org/10.1007/978-3-030-02278-5
Motaei J, Yaghmaie M, Pashaiefar H, Mousavi SA, Ghavamzadeh A, Ahmadvand M, Kerachian MA (2020) Differential microRNAs expression in acute graft-versus-host disease as potential diagnostic biomarkers. Bone Marrow Transplant. https://doi.org/10.1038/s41409-020-0949-7
Dweep H, Gretz N, Sticht C (2014) miRWalk database for miRNA-target interactions. Methods Mol Biol 1182:289–305. https://doi.org/10.1007/978-1-4939-1062-5_25
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10(1):1523. https://doi.org/10.1038/s41467-019-09234-6
Vlachos IS, Zagganas K, Paraskevopoulou Maria D, Georgakilas Georgios, Karagkouni Dimitra, Vergoulis Thanasis, Dalamagas Theodore, Hatzigeorgiou Artemis G (2015) DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Research 43(W1):W460–W466. https://doi.org/10.1093/nar/gkv403
Glaab E, Baudot A, Krasnogor N, Schneider R, Valencia A (2012) EnrichNet: network-based gene set enrichment analysis. Bioinformatics 28(18):i451–i457. https://doi.org/10.1093/bioinformatics/bts389
Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K (2018) Exosomal miRNA Signatures for Late-Onset Acute Graft-Versus-Host Disease in Allogenic Hematopoietic Stem Cell Transplantation. Int J Mol Sci 19 (9). https://doi.org/10.3390/ijms19092493
Paczesny S, Raiker N, Brooks S, Mumaw C (2013) Graft-versus-host disease biomarkers: omics and personalized medicine. Int J Hematol 98(3):275–292. https://doi.org/10.1007/s12185-013-1406-9
McDonald GB, Tabellini L, Storer BE, Lawler RL, Martin PJ, Hansen JA (2015) Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment. Blood 126(1):113–120. https://doi.org/10.1182/blood-2015-03-636753
Jalapothu D, Boieri M, Crossland RE, Shah P, Butt IA, Norden J, Dressel R, Dickinson AM, Inngjerdingen M (2016) Tissue-specific expression patterns of microRNA during acute graft-versus-host disease in the rat. Front Immunol 7:361. https://doi.org/10.3389/fimmu.2016.00361
Zhang C, Bai N, Huang W, Zhang P, Luo Y, Men S, Wen T, Tong H, Wang S, Tian YP (2016) The predictive value of selected serum microRNAs for acute GVHD by TaqMan MicroRNA arrays. Ann Hematol 95(11):1833–1843. https://doi.org/10.1007/s00277-016-2781-0
Crossland RE, Norden J, Kralj Juric M, Pearce KF, Lendrem C, Bibby LA, Collin M, Greinix HT, Dickinson AM (2017) Serum and extracellular vesicle microRNAs miR-423, miR-199, and miR-93* as biomarkers for acute graft-versus-host disease. Front Immunol 8:1446. https://doi.org/10.3389/fimmu.2017.01446
Yan S, Zhang H, Xie W, Meng F, Zhang K, Jiang Y, Zhang X, Zhang J (2017) Altered microRNA profiles in plasma exosomes from mesial temporal lobe epilepsy with hippocampal sclerosis. Oncotarget 8(3):4136–4146. https://doi.org/10.18632/oncotarget.13744
Atarod S, Norden J, Bibby LA, Janin A, Ratajczak P, Lendrem C, Pearce KF, Wang XN, O’Reilly S, Van Laar JM, Collin M, Dickinson AM, Crossland RE (2018) Differential microRNA expression levels in cutaneous acute graft-versus-host disease. Front Immunol 9:1485. https://doi.org/10.3389/fimmu.2018.01485
Hartwell MJ, Ozbek U, Holler E, Renteria AS, Major-Monfried H, Reddy P, Aziz M, Hogan WJ, Ayuk F, Efebera YA, Hexner EO, Bunworasate U, Qayed M, Ordemann R, Wolfl M, Mielke S, Pawarode A, Chen YB, Devine S, Harris AC, Jagasia M, Kitko CL, Litzow MR, Kroger N, Locatelli F, Morales G, Nakamura R, Reshef R, Rosler W, Weber D, Wudhikarn K, Yanik GA, Levine JE, Ferrara JL (2017) An early-biomarker algorithm predicts lethal graft-versus-host disease and survival. JCI Insight 2(3):e89798. https://doi.org/10.1172/jci.insight.89798
Kumar S, Reddy PH (2018) MicroRNA-455-3p as a potential biomarker for Alzheimer’s disease: an update. Front Aging Neurosci 10:41. https://doi.org/10.3389/fnagi.2018.00041
Jiang W, Zhang L, Guo Q, Wang H, Ma M, Sun J, Chen C (2019) Identification of the pathogenic biomarkers for hepatocellular carcinoma based on RNA-seq analyses. Pathol Oncol Res 25(3):1207–1213. https://doi.org/10.1007/s12253-019-00596-2
Zhang L, Mao J (2019) Long-chain noncoding RNA PVT1 gene polymorphisms are associated with the risk and prognosis of colorectal cancer in the Han Chinese Population. Genet Test Mol Biomarkers 23(10):728–736. https://doi.org/10.1089/gtmb.2019.0078
Sand M, Skrygan M, Sand D, Georgas D, Hahn SA, Gambichler T, Altmeyer P, Bechara FG (2012) Expression of microRNAs in basal cell carcinoma. Br J Dermatol 167(4):847–855. https://doi.org/10.1111/j.1365-2133.2012.11022.x
Chickooree D, Zhu K, Ram V, Wu HJ, He ZJ, Zhang S (2016) A preliminary microarray assay of the miRNA expression signatures in buccal mucosa of oral submucous fibrosis patients. J Oral Pathol Med 45(9):691–697. https://doi.org/10.1111/jop.12431
Yan S, Han B, Gao S, Wang X, Wang Z, Wang F, Zhang J, Xu D, Sun B (2017) Exosome-encapsulated microRNAs as circulating biomarkers for colorectal cancer. Oncotarget 8(36):60149–60158. https://doi.org/10.18632/oncotarget.18557
Yoo H, Yoo JK, Lee J, Lee DR, Ko JJ, Oh SH, Choo YK, Kim JK (2011) The hsa-miR-5787 represses cellular growth by targeting eukaryotic translation initiation factor 5 (eIF5) in fibroblasts. Biochem Biophys Res Commun 415(4):567–572. https://doi.org/10.1016/j.bbrc.2011.10.103
Chen W, Wang P, Lu Y, Jin T, Lei X, Liu M, Zhuang P, Liao J, Lin Z, Li B, Peng Y, Pan G, Lv X, Zhang H, Ou Z, Xie S, Lin X, Sun S, Ferrone S, Tannous BA, Ruan Y, Li J, Fan S (2019) Decreased expression of mitochondrial miR-5787 contributes to chemoresistance by reprogramming glucose metabolism and inhibiting MT-CO3 translation. Theranostics 9(20):5739–5754. https://doi.org/10.7150/thno.37556
Matboli M, Shafei AE, Azazy AE, Reda M, El-Khazragy N, Nagy AA, Ali MA, Sobhi M, Abdel-Rahman O (2018) Clinical evaluation of circulating miR-548a-3p and -20a expression in malignant pleural mesothelioma patients. Biomark Med 12(2):129–139. https://doi.org/10.2217/bmm-2017-0224
Kupetsky EA, Mathers AR, Ferris LK (2013) Anti-cytokine therapy in the treatment of psoriasis. Cytokine 61(3):704–712. https://doi.org/10.1016/j.cyto.2012.12.027
Hao JQ (2014) Targeting interleukin-22 in psoriasis. Inflammation 37(1):94–99. https://doi.org/10.1007/s10753-013-9715-y
Zhao X, Li R, Qiao M, Yan J, Sun Q (2018) MiR-548a-3p promotes keratinocyte proliferation targeting PPP3R1 after being induced by IL-22. Inflammation 41(2):496–504. https://doi.org/10.1007/s10753-017-0705-3
Gu G, Yang JZ, Zhang JQ, Sun LX (2019) Regulatory T cells in allogeneic hematopoietic stem cell transplantation: from the lab to the clinic. Cell Immunol 346:103991. https://doi.org/10.1016/j.cellimm.2019.103991
Di Ianni M, Del Papa B, Baldoni S, Di Tommaso A, Fabi B, Rosati E, Natale A, Santarone S, Olioso P, Papalinetti G, Giancola R, Accorsi P, Di Bartolomeo P, Sportoletti P, Falzetti F (2018) NOTCH and graft-versus-host disease Front Immunol 9:1825. https://doi.org/10.3389/fimmu.2018.01825
Zhang Y, Sandy AR, Wang J, Radojcic V, Shan GT, Tran IT, Friedman A, Kato K, He S, Cui S, Hexner E, Frank DM, Emerson SG, Pear WS, Maillard I (2011) Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood 117(1):299–308. https://doi.org/10.1182/blood-2010-03-271940
Tootoonchian R, Pak F, Ardekani AM, Sehati N, Abedi-Valugerdi M, Kokhaei P (2016) Evaluation of interleukin 12 and CD56+ lymphocyte cells in pediatric hematopoietic stem cell transplantation for early diagnosis of acute graft versus host disease. Transpl Immunol 39:25–29. https://doi.org/10.1016/j.trim.2016.10.002
Song Y, Hu B, Liu Y, Jin Z, Zhang Y, Lin D, Zhu Y, Lei L, Gong H, Mei Y, Teo HY, Wu D, Liu H (2018) IL-12/IL-18-preactivated donor NK cells enhance GVL effects and mitigate GvHD after allogeneic hematopoietic stem cell transplantation. Eur J Immunol 48(4):670–682. https://doi.org/10.1002/eji.201747177
Yang YG, Sykes M (1999) The role of interleukin-12 in preserving the graft-versus-leukemia effect of allogeneic CD8 T cells independently of GVHD. Leuk Lymphoma 33(5–6):409–420. https://doi.org/10.3109/10428199909058446
Williamson E, Garside P, Bradley JA, Mowat AM (1996) IL-12 is a central mediator of acute graft-versus-host disease in mice. J Immunol 157(2):689–699
Williamson E, Garside P, Bradley JA, More IA, Mowat AM (1997) Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J Immunol 159(3):1208–1215
Yu Y, Wang D, Liu C, Kaosaard K, Semple K, Anasetti C, Yu XZ (2011) Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORgammat in mice. Blood 118(18):5011–5020. https://doi.org/10.1182/blood-2011-03-340315
Bastian D, Wu Y, Betts BC, XZ Yu (2019) The IL-12 cytokine and receptor family in graft-vs.-host disease. Front Immunol 10:988. https://doi.org/10.3389/fimmu.2019.00988
Sykes M, Pearson DA, Taylor PA, Szot GL, Goldman SJ, Blazar BR (1999) Dose and timing of interleukin (IL)-12 and timing and type of total-body irradiation: effects on graft-vs.-host disease inhibition and toxicity of exogenous IL-12 in murine bone marrow transplant recipients. Biol Blood Marrow Transplant 5(5):277–284. https://doi.org/10.1016/S1083-8791(99)70002-9
Wang Y, Zhao X, Ye X, Luo H, Zhao T, Diao Y, Zhang H, Lv M, Zhang W, Huang X, Wan J (2015) Plasma microRNA-586 is a new biomarker for acute graft-versus-host disease. Ann Hematol 94(9):1505–1514. https://doi.org/10.1007/s00277-015-2414-z
Funding
This study was supported by grants from Dr. Marjan Yaghmaie (Grant# 95- 04–36-33688) and Dr. Mohammad Ahmadvand from Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran, and Student Research Committee (Proposal No. 971837), Mashhad University of Medical Sciences, Mashhad, Iran.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Motaei, J., Kerachian, M.A., Mousavi, S.A. et al. Circulating miR-455-3p, miR-5787, and miR-548a-3p as potential noninvasive biomarkers in the diagnosis of acute graft-versus-host disease: a validation study. Ann Hematol 100, 2621–2631 (2021). https://doi.org/10.1007/s00277-021-04573-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-021-04573-1