Çukurova Bölgesinde akut lenfoblastik lösemili çocuklarda vasküler endotelyal büyüme faktörü (VEGF-C) ve temel fibroblast büyüme faktörü (bFGF) plazma ekspresyonu ve metilasyon seviyeleri

Year 2020, Volume: 45 Issue: 2, 581 - 587, 30.06.2020

Nihal İnandıklıoglu , Osman Demirhan , İbrahim Bayram Atila Tanyeli

https://doi.org/10.17826/cumj.676515

Abstract

Amaç: Bu çalışmanın amacı akut lenfoblastik lösemili (ALL) çocuklarda vasküler endotel büyüme faktörü-C (VEGF-C) ve temel fibroblast büyüme faktörünün (bFGF) ekspresyon ve metilasyon düzeylerini belirlemekti.
Gereç ve Yöntem: Gerçek zamanlı kantitatif PCR ile yeni tanı almış olan 26 hasta ve 26 sağlıklı kontrolün periferik kan örneklerinde VEGF-C ve bFGF genlerinin mRNA ekspresyon profilleri ve metilasyon seviyelerini tespit ettik.
Bulgular: bFGF ekspresyon seviyesi ALL hastalarında kontrollere kıyasla anlamlı derecede artmıştı (4.23 kat). Ayrıca, VEGF-C ALL hastalarında kontrollere kıyasla anlamlı derecede azalmıştı (3.41 kat). VEGF-C (%6.88) ve bFGF (%16.64) genlerinin promotor bölgelerinin metilasyon oranı ALL hastalarında sağlıklı kontroller göre daha yüksekti.
Sonuç: Hastaların yıllar süren takibi sonucunda VEGF-C ve bFGF'de farklı zaman aralıklarında uzun süreli değişiklikler hastalık riski ile daha güçlü ilişkiler gösterebilir. Hem VEGF-C hem de bFGF ve ALL risk faktörleri ile güçlü bağlantılar kurmak için daha ileri çalışmalara ihtiyaç vardır.

Keywords

acute lymphoblastic leukemia, basic fibroblast growth factor, gene expression, methylation, vascular endothelial growth factor

Supporting Institution

ÇUKUROVA ÜNİVERSİTESİ

Project Number

TF2013BAP24

Thanks

Çukurova Üniversitesi Bilimsel Araştırma Projeleri Birimi projemizi desteklediği için teşekkür ederiz.

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

Abstract

Purpose: The aim of this study was to determine the expression and methylation levels of vascular endothelial growth factor-C (VEGF-C) and basic fibroblast growth factor (bFGF) in children with acute lymphoblastic leukemia (ALL).
Materials and Methods: We detected mRNA expression profiles and methylation levels of VEGF-C and bFGF genes in the peripheral blood samples of 26 patients with newly diagnosed ALL and 26 healthy controls by real-time quantitative PCR.
Results: The expression level of bFGF was significantly increased (4.23-fold) in ALL patients as compared with controls. Moreover, VEGF-C were significantly decreased (3.41-fold) in ALL patients as compared with controls. The methylation of the promoter region of VEGF-C (6.88%) and bFGF (16.64%) genes was higher in ALL patients than in healthy controls.
Conclusion: Long-term changes in VEGF-C and bFGF at different time intervals as a result of years of follow-up of patients may show stronger associations with disease risk. Further studies are required to establish strong links with both VEGF-C and bFGF, and ALL risk factors. 

Keywords

Acute lymphoblastic leukemia, basic fibroblast growth factor

Project Number

TF2013BAP24

References

• 1. Moehler TM, Ho AD, Goldschmidt H, Barlogie B. Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol 2003;45:227-244. 2. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011-1027. 3. Aguayo A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M, et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood 1999;94:3717-3721. 4. Salven P, Orpana A, Teerenhovi L, Joensuu H. Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood 2000;96:3712-3718. 5. Ribatti D, Scavelli C, Roccaro AM, Crivellato E, Nico B, Vacca A. Hematopoietic cancer and angiogenesis. Stem Cells Dev 2004;13:484-495. 6. Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005;105:1383–1395. 7. Faderl S, Do KA, Johnson MM, Keating M, O'brien S, Jilani I, et al. Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia. Blood 2005;106:4303-4307. 8. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001;7:192-198. 9. Dias S, Choy M, Alitalo K, Rafii S. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4(VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 2002;99: 2179-2184. 10. 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. Am J Pathol 1997;150:815-821. 11. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985;103:620-625. 12. Rothe G. Schmitz G. Consensus protocol for the flow cytometric immunophenotyping of hematopoietic malignancies. Working Group on Flow Cytometry and Image Analysis. Leukemia, 1996;10.5:877-895. 13. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423-1425. 14. Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 2001;7:199-205. 15. Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, et al. Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci USA 1998;95:14389–14394. 16. Fielder W, Graeven U, Ergun S, S Verago, N Kilic, M Stockschläder , et al. Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. Leukemia 1997;11:1234-1237. 17. De Jonge HJM, Valk PJM, Veeger NJGM, ter Elst A, den Boer ML, Cloos J, et al. High VEGFC expression is associated with unique gene expression profiles and predicts adverse prognosis in pediatric and adult acute myeloid leukemia. Blood 2010;116:1747-1754. 18. Aliparasti MR, Almasi S, Sanaat Z, Movasaghpoor A, Khalili-Dizaji R, Sadeghi-Bazargani H. Gene expression of VEGF-A and VEGF-C in peripheral blood mononuclear cells of Iranian patients with acute myeloid leukemia. Turk J Hematol 2013;30(2):137-143. 19. Nowicki M, Ostalska‐Nowicka D, Kaczmarek E, B Miskowiak, M Witt. Vascular endothelial growth factor C a potent risk factor in childhood acute lymphoblastic leukemia: an immunocytochemical approach. Histopathology 2006;49(2):170-177. 20. Stachel D, Albert M, Meilbeck R, Paulides M, Schmid I. Expression of angiogenic factors in childhood B-cell precursor acute lymphoblastic leukemia. Oncol Rep 2007;17:147-152. 21. Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000;95:309-313. 22. Lyu CJ, Rha SY, Won SC. Clinical role of bone marrow angiogenesis in childhood acute lymphocytic leukemia. Yonsei Med J 2007;48:171-175. 23. Yetgin S, Yenicesu I, Cetin M, Tuncer M. Clinical importance of serum vascular endothelial and basic fibroblast growth factors in children with acute lymphoblastic leukemia. Leuk Lymphoma 2001;42:83-88. 24. Ball MP, Li JB, Gao Y, Lee JH, LeProust EM, Park IH, et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol 2009;27:361-368. 25. Dai W, Zeller C, Masrour N, Siddiqui N, Paul J, Brown R. Promoter CPG island methylation of genes in key cancer pathways associates with clinical outcome in high grade serous ovarian cancer. Clin Cancer Res 2013;19(20): 5788-5797. 26. Matsumura S, Oue N, Mitani Y, Kitadai Y, Yasui W. DNA demethylation of vascular endothelial growth factor‐C is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer. Int J Cancer 2007;120(8):1689-1695. 27. Jung GA, Shin BS, Jang YS, Sohn JB, Woo SR, Kim JE, et al. Methylation of eukaryotic elongation factor 2 induced by basic fibroblast growth factor via mitogen-activated protein kinase. Exp Mol Med 2011;43(10):550-560. 28. Van Vliet J, Oates NA, Whitelaw, E. Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 2007;64:1531-1538. 29. Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene 2002;21:5400-5413. 30. Ushijima T. Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 2005;5(3):223–231.