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MiR-34a-5p’NİN AŞIRI İFADE EDİLEN AML İLİŞKİLİ GENLER ÜZERİNDEKİ ETKİSİ

Yıl 2023, Cilt: 86 Sayı: 1, 59 - 68, 31.01.2023
https://doi.org/10.26650/IUITFD.1168793

Öz

Amaç: Akut miyeloid lösemi (AML) ölümcül bir lösemi türüdür. AML ilişkili genlerin ekspresyonu sadece genetik değişikliklerle değil aynı zamanda mikroRNA’lar (miRNA’lar) gibi çeşitli epigenetik faktörlerle de değiştirilebilir. MiRNA’lar birçok genin ifade seviyesini değiştirerek hücrede oldukça kritik görevler yapabilmektedir. miRNA ve hedef genleri arasındaki etkileşimin tespit edilmesi, hastalığın moleküler mekanizmasının aydınlatılması açısından oldukça önemlidir. Çalışmamızda AML dahil birçok kanserde tümör baskılayıcı role sahip miR-34a-5p’nin AML hücre proliferasyonu üzerindeki etkisi ve AML ilişkili genlerin ifade değişimindeki rolü araştırılmıştır. Gereç ve Yöntem: Leukemia Gene and Literature Database web sitesi (http://soft.bioinfo-minzhao.org/lgl/)’de, lösemi ile ilişkili genleri içeren 600’den fazla AML ile ilgili gen bulunmaktadır. Bu web sayfasında yer alan miR-34a-5p’nin potansiyel hedef genlerini tanımlamak için yaptığımız bu çalışmada miRDB veri tabanı kullanılmıştır. Sonrasında miRWalk, miRTarbase, Tarbase ve miRNet araçlarıyla doğrulanmıştır. PPI etkileşimleri, yolak analizi, çeşitli biyoinformatik araçlar kullanılarak tanımlanmıştır. İn vitro olarak miR-34a-5p’nin AML hücreleri üzerindeki etkisi belirlenip NOTCH2, IGF1R, SKP2 ve CDC25A genlerinin mimik miR-34a-5p ile transfekte edilmiş NB4 ve HL60 hücrelerinde ekspresyonu araştırılmıştır. Bulgular: Çeşitli biyoinformatik araçlar kullanılarak miR-34a-5p tarafından hedeflenebilecek 44 AML ilişkili gen belirlenmiştir. Sonrasında yapılan in vitro çalışmada miR-34a-5p ile transfekte edilen hücrelerde proliferasyonun istatistiksel olarak anlamlı şekilde baskılandığı gözlenmiştir (48 saat HL60 hücreleri p=0,00011; NB4 hücreleri p=0,0031 ve 96 saat HL60 hücreleri p=0,00013; NB4 p=0,00018). miR-34a-5p mimik transfekte edilen NB4 ve HL60 hücrelerinde NOTCH2, IGF1R, SKP2 ve CDC25A mRNA ifade seviyelerinin kontrol gruplarına göre anlamlı şekilde azaldığı tespit edilmiştir (HL60 hücrelerinde sırasıyla (p=0,003; p=0,02; p=0,01; p=0,0009) ve NB4 hücrelerinde sırasıyla p=0,02; p=0,02; p=0,01; p=0,0007). Sonuç: miR-34a-5p; NOTCH2, IGF1R, SKP2 ve CDC25A gibi birçok geni hedefleyerek AML hücre proliferasyonunu inhibe edebilir. Bu genler ile miR-34a-5p arasındaki ilişkiyi net bir şekilde belirleyebilmek için daha ileri tekniklerle farklı çalışmaların yapılmasına ihtiyaç vardır. Çalışma sonuçlarımız, miRNA-hedef gen ilişkisi araştırılırken uygun biyoinformatik araçlarla in vitro yöntemlerin birlikte başarıyla kullanılabileceğini göstermektedir.

Destekleyen Kurum

Herhangi bir kurumdan destek alınmamıştır

Kaynakça

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  • 6. Piovesan A, Antonaros F, Vitale L, Strippoli P, Pelleri MC, Caracausi M. Human protein-coding genes and gene feature statistics in 2019. BMC Res Notes 2019;12(1):315. [CrossRef] google scholar
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THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES

Yıl 2023, Cilt: 86 Sayı: 1, 59 - 68, 31.01.2023
https://doi.org/10.26650/IUITFD.1168793

Öz

Objective: Acute myeloid leukemia (AML) is a deadly type of leukemia. The expression of AML-related genes may be altered not only by genetic changes but also by various epigenetic factors such as microRNAs (miRNAs). The expression levels of many genes can be altered by miRNAs. The detection of miRNA’s target genes is critical for an understanding of the disease’s molecular mechanism. In this study possible target genes of miR-34a-5p in AML were determined and the effect of the relationship between miR-34a-5p and target genes on the cancer process was investigated. Materials and Methods: Leukemia Gene and Literature Database web tool (http://soft.bioinfo-minzhao.org/lgl/) includes a useful leukemia gene and literature da. There are more than 600 AML-related genes on this database. In the present study, in order to define the potential target genes of miR-34a-5p on the database, we used miRDB tool and then confirmed the findings using miRWalk, miRTarbase, Tarbase and miRNet tools. Defined miR-34a-5p AML related genes were verified by the DisGeNET platform. A Protein-Protein Interaction (PPI) network analysis of the genes was conducted using several bioinformatics tools. The effect of miR-34a-5p on cell proliferation was investigated by transfecting mimic miR-34a-5p into HL60 and NB4 cells. The mRNA expressions of NOTCH2, IGF1R, SKP2 and CDC25A genes were investigated in miR-34a-5p transfected NB4 and HL60 cells and control groups. Results: Using bioinformatics tools we determined 44 AMLrelated genes that could be targeted by miR-34a-5p. According to our in vitro study results statistically significant suppression of proliferation was observed in miR-34a-5p transfected cells (48h HL60 cells p=0.00011; NB4 cells p=0.0031 and 96h HL60 cells p=0.00013; NB4 p=0.00018). It was also found that NOTCH2, IGF1R, SKP2 and CDC25A mRNA expressions were down regulated in miR-34a-5p mimic-transfected HL60 cells (p=0.003; p=0.02; p=0.01; p=0.0009 respectively) and NB4 cells (p=0.02; p=0.02; p=0.01; p=0.0007 respectively) compared to the control groups. Conclusion: miR-34a-5p may inhibit AML cell proliferation by targeting many genes like NOTCH2, IGF1R, SKP2 and CDC25A. The results of our study indicate that appropriate bioinformatics tools and in vitro methods can successfully be used together when investigating the relationship between miRNAs and target genes. Further studies are required to determine the detailed relationship between these genes and miR-34a-5p.

Kaynakça

  • 1. Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM. Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev 2019;36:70-87. [CrossRef] google scholar
  • 2. Swaminathan M, Wang ES. Novel therapies for AML: a round-up for clinicians. Expert Rev Clin Pharmacol 2020;13(12):1389-400. [CrossRef] google scholar
  • 3. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115(3):453-74. [CrossRef] google scholar
  • 4. Capik O, Sanli F, Kurt A, Ceylan O, Suer I, Kaya M, et al. CASC11 promotes aggressiveness of prostate cancer cells through miR-145/IGF1R axis. Prostate Cancer Prostatic Dis 2021;24(3):891-902. [CrossRef] google scholar
  • 5. Kaya M, Karatas OF. The relationship between larynx cancer and MicroRNAs. Van medical journal 2020;27(4):535-41. [CrossRef] google scholar
  • 6. Piovesan A, Antonaros F, Vitale L, Strippoli P, Pelleri MC, Caracausi M. Human protein-coding genes and gene feature statistics in 2019. BMC Res Notes 2019;12(1):315. [CrossRef] google scholar
  • 7. Alles J, Fehlmann T, Fischer U, Backes C, Galata V, Minet M, et al. An estimate of the total number of true human miRNAs. Nucleic Acids Res 2019;47(7):3353-64. [CrossRef] google scholar
  • 8. Suer I, Kaya M, Ozgur E. The effect of miR-34a-5p and miR-145-5p ectopic expression on cell proliferation and target gene expression in the MDA-MB-231 Cell Line. NKMJ 2021;9(2):166-73. [CrossRef] google scholar
  • 9. Peterson SM, Thompson JA, Ufkin ML, Sathyanarayana P, Liaw L, Congdon CB. Common features of microRNA target prediction tools. Front Genet 2014;5:23. [CrossRef] google scholar 10. Leclercq M, Diallo AB, Blanchette M. Prediction of human miRNA target genes using computationally reconstructed ancestral mammalian sequences. Nucleic Acids Res 2017;45(2):556-66. [CrossRef] google scholar
  • 11. Chen P, Feng Y, Zhang H, Shi X, Li B, Ju W, et al. MicroRNA-192 inhibits cell proliferation and induces apoptosis in human breast cancer by targeting caveolin 1. Oncol Rep 2019;42(5):1667-76. [CrossRef] google scholar
  • 12. Miller PG, Al-Shahrour F, Hartwell KA, Chu LP, Jârâs M, Puram RV, et al. In Vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling. Cancer Cell 2013;24(1):45-58. [CrossRef] google scholar
  • 13. Pierce A, Whetton AD, Meyer S, Ravandi-Kashani F, Borthakur G, Coombes KR, et al. Transglutaminase 2 expression in acute myeloid leukemia: association with adhesion molecule expression and leukemic blast motility. Proteomics 2013;13(14):2216-24. [CrossRef] google scholar
  • 14. Guzman ML, Yang N, Sharma KK, Balys M, Corbett CA, Jordan CT, et al. Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia. Mol Cancer The 2014;13(8):1979-90. [CrossRef] google scholar
  • 15. Favreau AJ, Cross EL, Sathyanarayana P. miR-199b-5p directly targets PODXL and DDR1 and decreased levels of miR-199b-5p correlate with elevated expressions of PODXL and DDR1 in acute myeloid leukemia. Am J Hematol 2012;87(4):442-6. [CrossRef] google scholar
  • 16. Wallace JA, O’Connell RM. MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts. Blood 2017;130(11):1290-301. [CrossRef] google scholar
  • 17. Singh G, Sharma SK, Singh SK. miR-34a negatively regulates cell cycle factor Cdt2/DTL in HPV infected cervical cancer cells. BMC Cancer 2022;22(1):777. [CrossRef] google scholar
  • 18. Roy S, Levi E, Majumdar AP, Sarkar FH. Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF. J Hematol Oncol 2012;5:58. [CrossRef] google scholar
  • 19. Kalfert D, Ludvikova M, Pesta M, Ludvik J, Dostalova L, Kholova I. Multifunctional roles of miR-34a in cancer: a review with the emphasis on head and neck squamous cell carcinoma and thyroid cancer with clinical implications. Diagnostics (Basel) 2020;10(8):563. [CrossRef] google scholar
  • 20. Xiong S, Hu M, Li C, Zhou X, Chen H. Role of miR-34 in gastric cancer: From bench to bedside (Review). Oncol Rep 2019;42(5):1635-46. [CrossRef] google scholar
  • 21. Slabakova E, Culig Z, Remsik J, Soucek K. Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis 2017;8(10):e3100. [CrossRef] google scholar
  • 22. Rao DS, O’Connell RM, Chaudhuri AA, Garcia-Flores Y, Geiger TL, Baltimore D. MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1. Immunity 2010;33(1):48-59. [CrossRef] google scholar
  • 23. Huang Y, Zou Y, Lin L, Ma X, Chen H. Identification of serum miR-34a as a potential biomarker in acute myeloid leukemia. Cancer Biomark 2018;22(4):799-805. [CrossRef] google scholar
  • 24. Mraz M, Malinova K, Kotaskova J, Pavlova S, Tichy B, Malcikova J, et al. miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 2009;23(6):1159-63. [CrossRef] google scholar
  • 25. Li WJ, Wang Y, Liu R, Kasinski AL, Shen H, Slack FJ, et al. MicroRNA-34a: potent tumor suppressor, cancer stem cell inhibitor, and potential anticancer therapeutic. Front Cell Dev Biol 2021;9:640587. [CrossRef] google scholar
  • 26. Pulikkan JA, Peramangalam PS, Dengler V, Ho PA, Preudhomme C, Meshinchi S, et al. C/EBPa regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations. Blood 2010;116(25):5638-49. [CrossRef] google scholar
  • 27. Liu X, Li H. Diagnostic Value of miR-34a in Bone Marrow Mononuclear Cells of Acute Myeloid Leukemia Patients. Clin Lab 2020;66(3). [CrossRef] google scholar
  • 28. Ray D, Kiyokawa H. CDC25A phosphatase: a rate-limiting oncogene that determines genomic stability. Cancer Res 2008;68(5):1251-3. [CrossRef] google scholar
  • 29. Xiu MX, Liu YM. The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. Am J Cancer Res 2019;9(5):837-54. google scholar
  • 30. Bretones G, Acosta JC, Caraballo JM, Ferrándiz N, Gómez-Casares MT, Albajar M, et al. SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells. J Biol Chem 2011;286(11):9815-25. [CrossRef] google scholar
  • 31. Alfaro-Arnedo E, López IP, Piñeiro-Hermida S, Canalejo M, Gotera C, Sola JJ, et al. IGF1R acts as a cancer-promoting factor in the tumor microenvironment facilitating lung metastasis implantation and progression. Oncogene 2022;41(28):3625-39. [CrossRef] google scholar
  • 32. Zhang W, Cao L, Sun Z, Xu J, Tang L, Chen W, et al. Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation. Cell Cycle 2016;15(10):1344-51. [CrossRef] google scholar
  • 33. Chen S, Tang Y, Yang C, Li K, Huang X, Cao J. Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL-6 in vitro and in vivo. Int J Mol Med 2020;45(3):743-52. [CrossRef] google scholar
  • 34. Takam Kamga P, Bassi G, Cassaro A, Midolo M, Di Trapani M, Gatti A, et al. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia. Oncotarget 2016;7(16):21713-27. [CrossRef] google scholar
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Toplam 52 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Kurumları Yönetimi
Bölüm ARAŞTIRMA
Yazarlar

Murat Kaya 0000-0003-2241-7088

Ilknur Suer 0000-0003-1954-4190

Yayımlanma Tarihi 31 Ocak 2023
Gönderilme Tarihi 31 Ağustos 2022
Yayımlandığı Sayı Yıl 2023 Cilt: 86 Sayı: 1

Kaynak Göster

APA Kaya, M., & Suer, I. (2023). THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES. Journal of Istanbul Faculty of Medicine, 86(1), 59-68. https://doi.org/10.26650/IUITFD.1168793
AMA Kaya M, Suer I. THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES. İst Tıp Fak Derg. Ocak 2023;86(1):59-68. doi:10.26650/IUITFD.1168793
Chicago Kaya, Murat, ve Ilknur Suer. “THE EFFECT OF MiR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES”. Journal of Istanbul Faculty of Medicine 86, sy. 1 (Ocak 2023): 59-68. https://doi.org/10.26650/IUITFD.1168793.
EndNote Kaya M, Suer I (01 Ocak 2023) THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES. Journal of Istanbul Faculty of Medicine 86 1 59–68.
IEEE M. Kaya ve I. Suer, “THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES”, İst Tıp Fak Derg, c. 86, sy. 1, ss. 59–68, 2023, doi: 10.26650/IUITFD.1168793.
ISNAD Kaya, Murat - Suer, Ilknur. “THE EFFECT OF MiR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES”. Journal of Istanbul Faculty of Medicine 86/1 (Ocak 2023), 59-68. https://doi.org/10.26650/IUITFD.1168793.
JAMA Kaya M, Suer I. THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES. İst Tıp Fak Derg. 2023;86:59–68.
MLA Kaya, Murat ve Ilknur Suer. “THE EFFECT OF MiR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES”. Journal of Istanbul Faculty of Medicine, c. 86, sy. 1, 2023, ss. 59-68, doi:10.26650/IUITFD.1168793.
Vancouver Kaya M, Suer I. THE EFFECT OF miR-34a-5p ON OVEREXPRESSED AML ASSOCIATED GENES. İst Tıp Fak Derg. 2023;86(1):59-68.

Contact information and address

Addressi: İ.Ü. İstanbul Tıp Fakültesi Dekanlığı, Turgut Özal Cad. 34093 Çapa, Fatih, İstanbul, TÜRKİYE

Email: itfdergisi@istanbul.edu.tr

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