Changes in the expression and methylation levels of the MMP-2, MMP-9, TIMP-1, TIMP-2 and VEGF-A genes in children with acute lymphoblastic leukemia

Year 2021, Volume: 46 Issue: 2, 825 - 833, 30.06.2021

Nihal İnandıklıoglu , Osman Demirhan , İbrahim Bayram , Atila Tanyel,i

Abstract

Purpose: The aim of this article is to show the expression and methylation levels of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and vascular endothelial growth factor (VEGF)genes in patients diagnosed with childhood acute lymphoblastic leukemia (ALL) and their relationship with clinical findings.
Materials and Methods: In this study, we determined the expression level and methylation percentage of MMP2, MMP9, TIMP1, TIMP2 and VEGF-A genes between patients with childhood ALL and healthy children. Expression and methylation analyzes were performed by RT-PCR. The results of MMP2, MMP9, TIMP1, TIMP2, VEGF-A and other clinical parameters were compared between the two groups.
Results: The expression levels of MMP2 (2.55-fold), MMP9 (5.06-fold), TIMP1 (2.91-fold) and VEGF-A (4.76-fold) was significantly higher in the patients, but the same results were not found for TIMP-2. The methylation levels of MMP2 (29.74%), MMP9 (30.98%), TIMP2 (11.91%) and VEGF-A (6.55%) were significantly higher in the patients than in the controls.
Conclusion: MMP2, MMP9 and VEGF-A genes have high expression and methylation levels. These results make this complex structure intriguing in childhood ALL for further studies and reinforce the emphasis that it should be investigated.

Keywords

Acute lymphoblastic leukemia, MMP, TIMP, VEGF-A

Supporting Institution

This work was supported by Çukurova University Scientific Research Projects Unit

Project Number

TF2012D1

Thanks

We would like to thank the Scientific Research Unit of Çukurova University for supporting our project.

Akut lenfoblastik lösemili çocuklarda MMP-2, MMP-9, TIMP-1, TIMP-2 ve VEGF-A genlerinin ekspresyon ve metilasyon seviyelerindeki değişiklikler

Abstract

Amaç: Bu makalenin amacı, çocukluk çağı akut lenfoblastik lösemi (ALL) tanısı almış hastalarda matriks metaloproteinazlar (MMP'ler), doku inhibitörleri metaloproteinazlar (TIMP'ler) ve vasküler endotelyal büyüme faktörünün (VEGF) genlerinin ekspresyon ve metilasyon düzeylerini ve bunların klinik bulgularla ilişkisini göstermektir.
Gereç ve Yöntem: Bu çalışmada, çocukluk çağı ALL hastaları ile sağlıklı çocuklar arasında MMP2, MMP9, TIMP1, TIMP2 ve VEGF-A genlerinin ekspresyon düzeyini ve metilasyon yüzdesini belirledik. Ekspresyon ve metilasyon analizleri RT-PCR ile yapıldı. MMP2, MMP9, TIMP1, TIMP2, VEGF-A ve diğer klinik parametrelerin sonuçları iki grup arasında karşılaştırıldı.
Bulgular: Hastalarda MMP2 (2.55-kat), MMP9 (5.06-kat), TIMP1 (2.91-kat) ve VEGF-A (4.76-kat) ekspresyon seviyeleri anlamlı olarak yüksekti, ancak aynı sonuçlar TIMP-2 için geçerli değildi. Hastalarda MMP2 (% 29.74), MMP9 (% 30.98), TIMP2 (% 11.91) ve VEGF-A (% 6.55) metilasyon düzeyleri kontrollere göre anlamlı derecede yüksekti.
Sonuç: Verilerimiz MMP2, MMP9 ve VEGF-A genlerinin yüksek ekspresyon ve metilasyon seviyelerine sahip olduğunu gösterdi. Bu sonuçlar, çocukluk çağı ALL’de bu karmaşık yapıyı daha ileri çalışmalar için ilgi çekici hale getirmekte ve araştırılması gerektiği vurgusunu pekiştirmektedir.

Keywords

Akut lenfoblastik lösemi, MMP, TIMP, VEGF-A.

Project Number

TF2012D1

References

• Board, PPTE. Childhood acute lymphoblastic leukemia treatment (PDQ). In PDQ Cancer Information Summaries [Internet]. National Cancer Institute (US). 2019.
• Marech I, Leporini C, Ammendola M, Porcelli M, Gadaleta CD, Russo E, et al. Classical and non-classical proangiogenic factors as a target of antiangiogenic therapy in tumor microenvironment. Cancer letters. 2016;380(1):216–226.
• Medinger M, Passweg J. Role of tumour angiogenesis in haematological malignancies. Swiss medical weekly. 2014;144:w14050.
• Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. The American journal of pathology. 1997;150(3):815–821.
• Poyer F, Coquerel B, Pegahi R, Cazin L, Norris V, Vannier JP, et al. Secretion of MMP-2 and MMP-9 induced by VEGF autocrine loop correlates with clinical features in childhood acute lymphoblastic leukemia. Leukemia research. 2009;33(3):407–417.
• Rundhaug JE. Matrix metalloproteinases and angiogenesis. Journal of cellular and molecular medicine. 2005;9(2):267–285.
• Lin CM, Zeng YL, Xiao M, Mei XQ, Shen LY, Guo MX. The Relationship Between MMP-2 -1306C>T and MMP-9 -1562C>T Polymorphisms and the Risk and Prognosis of T-Cell Acute Lymphoblastic Leukemia in a Chinese Population: A Case-Control Study. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2017;42(4):1458–1468.
• Scrideli CA, Cortez MA, Yunes JA, Queiróz RG, Valera ET, da Mata JF, et al. mRNA expression of matrix metalloproteinases (MMPs) 2 and 9 and tissue inhibitor of matrix metalloproteinases (TIMPs) 1 and 2 in childhood acute lymphoblastic leukemia: potential role of TIMP1 as an adverse prognostic factor. Leukemia research. 2010:34(1);32–37.
• Salah NY. Vascular endothelial growth factor (VEGF), tissue inhibitors of metalloproteinase-1 (TIMP-1) and nail fold capillaroscopy changes in children and adolescents with Gaucher disease; relation to residual disease severity. Cytokine. 2020;133:155120.
• Padró T, Ruiz S, Bieker R, Bürger H, Steins M, Kienast J, et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood. 2000;95(8):2637–2644.
• Wang X, Khalil RA. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Advances in pharmacology. 2018;81:241–330.
• Kuittinen O, Savolainen ER, Koistinen P, Möttönen M, Turpeenniemi-Hujanen T. MMP-2 and MMP-9 expression in adult and childhood acute lymphatic leukemia (ALL). Leukemia research. 2001;25(2):125–131.
• Schneider P, Costa O, Legrand E, Bigot D, Lecleire S, Grassi V, et al. In vitro secretion of matrix metalloprotease 9 is a prognostic marker in childhood acute lymphoblastic leukemia. Leukemia research. 2010;34(1):24–31.
• Zou J, Li P, Lu F, Liu N, Dai J, Ye J, et al. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells. Journal of hematology & oncology. 2013);6:3.
• Suminoe A, Matsuzaki A, Hattori H, Koga Y, Ishii E, Hara T. Expression of matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) genes in blasts of infant acute lymphoblastic leukemia with organ involvement. Leukemia research. 2007;31(10):1437–1440.
• Verma D, Zanetti C, Godavarthy PS, Kumar R, Minciacchi VR, Pfeiffer J, et al. Bone marrow niche-derived extracellular matrix-degrading enzymes influence the progression of B-cell acute lymphoblastic leukemia. Leukemia. 2020;34(6):1540–1552.
• Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer metastasis reviews. 2006;25(1):9–34.
• Lambert E, Dassé E, Haye B, Petitfrère E. TIMPs as multifacial proteins. Critical reviews in oncology/hematology. 2004;49(3):187–198.
• Guedez L. Stetler-Stevenson WG. The prognostic value of TIMP-1 in multiple myeloma. Leukemia research. 2010;34(5):576–577.
• Guedez L, Courtemanch L, Stetler-Stevenson M. Tissue inhibitör of metalloproteinase (timp)-1 induces differentiation and an antiapoptotic phenotype in germinal center b cells. Blood. 1998;92:1342.
• Kováč M. Vášková M, Petráčková D, Pelková V, Mejstříková E, Kalina T, et al. Cytokines, growth, and environment factors in bone marrow plasma of acute lymphoblastic leukemia pediatric patients. European cytokine network. 2014;25(1):8–13.
• Stetler-Stevenson M, Mansoor A, Lim M, Fukushima P, Kehrl J, Marti G, et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in reactive and neoplastic lymphoid cells. Blood. 1997;89:1708–15.
• Forte D, Salvestrini V, Corradi G, Rossi L, Catani L, Lemoli RM, et al. The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling. Oncotarget. 2017;8(2):2261–2274.
• Kossakowska AE, Urbanski SJ, Watson A, Hayden LJ, Edwards DR. Patterns of expression of metalloproteinases and their inhibitors in human malignant lymphomas. Oncol Res. 1993;5:19–28.
• Aguayo A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M, Giles F, Estrov Z, Barlogie B, Albitar M. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood. 1999;94:3717-21.
• Molica S, Santoro R, Digiesi G, Dattilo A, Levato D, Muleo G. Vascular endothelial growth factor isoforms 121 and 165 are expressed on B-chronic lymphocytic leukemia cells. Haematologica. 2000;85(10):1106-1108.
• Münch V, Trentin L, Herzig J, Demir S, Seyfried F, Kraus JM, et al. Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor. Blood. 2017;130(5):643–654.
• Poyer F, Coquerel B, Pegahi R, Cazin L, Norris V, Vannier JP, et al. Secretion of MMP-2 and MMP-9 induced by VEGF autocrine loop correlates with clinical features in childhood acute lymphoblastic leukemia. Leukemia research. 2009;33(3):407–417.
• 29. Schneider P, Vasse M, Legrand E, Callat MP, Vannier JP. Have urinary levels of the angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, a prognostic value in childhood acute lymphoblastic leukaemia?. British journal of haematology. 2003;122(1):163–164.
• Weis S, Cui J, Barnes L, Cheresh D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. The Journal of cell biology. 2004;167(2):223–229.
• Fragoso R, Pereira T, Wu Y, Zhu Z, Cabeçadas J, Dias S. VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease. Blood. 2006;107(4):1608–1616.
• Nordlund J, Syvänen AC. Epigenetics in pediatric acute lymphoblastic leukemia. Seminars in cancer biology. 2018;51:129–138.
• İnandıklıoglu N, Demi̇rhan O, Bayram İ, Tanyeli̇ A. Plasma expression and methylation levels of vascular endothelial growth factor (VEGF-C) and basic fibroblast growth factor (bFGF) in children with acute lymphoblastic leukemia in Çukurova Region, Turkey. Cukurova Medical Journal. 2020;45:581-587.
• Hogan LE, Meyer JA, Yang J, Wang J, Wong N, Yang W, et al. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. Blood. 2011;118(19):5218–5226.
• Kunz JB, Rausch T, Bandapalli OR, Eilers J, Pechanska P, Schuessele S, et al. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation. Haematologica. 2015;100(11):1442–1450.