Investigation of the target genes of BLV miRNAs and the expression levels of miR-B4-3p and miR-B2-5p in cattle infected with Bovine Leukemia Virus

Document Type : Original Article

Authors

1 Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran,Iran

2 Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

3 Department of Molecular Medical Genetics, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

Abstract

Bovine Leukemia Virus (BLV) is an oncogenic retrovirus of the genus Deltaretrovirus. The genome of BLV encodes a cluster of 10 mature microRNAs (miRNAs). Considering the importance of miRNAs in regulating gene expression, it seems that each of the miRNAs of BLV plays a vital role in the process of pathogenesis and tumorigenesis of the virus. First, sequences of each of the miRNAs of BLV were selected and downloaded from the miRBase database. The sequences were then investigated using TargetScan and miRWalk to identify target genes of each of the mature miRNAs of the virus. Second, the expression levels of the two miRNAs with the highest number of target genes in B lymphocytes and lymphoid tissues were evaluated using qPCR and were compared between cattle with different forms of BLV infection: PL form was compared to ‎aleukemic (AL) form (Group 1) and BLV+ with normal lymph nodes were compared to lymphosarcoma form (Group 2). We identified a total of 1595 target genes of the micro RNAs. The miRNAs with the highest target genes included miR-B4-3p with 760 and B2-5p with 102 target genes. In the second phase, miRNA expression in BLV-infected animals was investigated. The Fold Change (FC) values for miR-B4-3p and miR-B2-5p in group 1 were 22 and 67, respectively. In the second group, the FCs for miR-B4-3p and miR-B2-5p were 47 and 133, respectively. The expression was significantly higher in persistent lymphocytosis (PL) cattle in group one and lymphosarcoma cattle in group two.

Keywords


  1. Fenner FJ, Auslan BR, Mims CA. Fenner’s Veterinary Virology. 5th USA, Academic Press is an imprint of Elsevier. 2017; 266-295. doi: 10.1016/B978-0-12-800946-8.00001-5.
  2. Juliarena MA, Barrios CN, Lützelschwab CM, et al. Bovine leukemia virus: current perspectives. Virus Adapt Treat 2017; 9: 13-26.
  3. Abdala A, Alvarez I, Brossel H, et al. BLV: lessons on vaccine development. Retrovirology 2019; 16(1): 26. doi: 10.1186/s12977-019-0488-8
  4. Barez PY, de Brogniez A, Carpentier A, et al. Recent Advances in BLV Research. Viruses 2015; 7(11):
    6080-6088.
  5. Polat M, Takeshima SN, Aida Y. Epidemiology and genetic diversity of bovine leukemia virus. Virol J 2017; 14(1):209. doi: 10.1186/s12985-017-0876-4.
  6. Sun Q, Yang Z, Li P, et al. A novel miRNA identified in GRSF1 complex drives the metastasis via the PIK3R3/AKT/NF-κB and TIMP3/MMP9 pathways in cervical cancer cells. Cell Death Dis. 2019;10(9). doi:10.1038/s41419-019-1841-5.
  7. Martinez Cuesta L, Lendez PA, Nieto Farias MV, et al. Can bovine leukemia virus be related to human breast cancer? a review of the evidence. J Mammary Gland Biol Neoplasia 2018; 23(3): 101-107.
  8. Buehring GC, Shen HM, Jensen HM, et al. Exposure to bovine leukemia virus is associated with breast cancer: a case-control study. PLoS One 2015; 10(9): e0134304. doi:10.1371/journal.pone.0134304.
  9. Khalilian M, Hosseini SM, Madadgar O. Bovine leukemia virus detected in the breast tissue and blood of Iranian women. Microb Pathog 2019;135: 103566. doi:10.1016/j.micpath.2019.103566.
  10. Durkin K, Rosewick N, Artesi M, et al. Identification and characterization of novel bovine leukemia virus (BLV) antisense transcripts reveals their constitutive expression in leukemic and pre-leukemic clones. bioRxiv 2016: 039255. doi: 10.1101/039255.
  11. Zyrianova IM, Kovalchuk SN. Bovine leukemia virus tax gene/Tax protein polymorphism and its relation to Enzootic Bovine Leukosis. Virulence. 2020;11(1):80-87. doi:10.1080/21505594.2019.1708051
  12. Hemmatzadeh F, Reza Tofighi E, et al. Investigation of env gene of bovine leukaemia virus in infected cows. Indian Vet J. 2008; 85(9): 924-926.
  13. Li X, Zou X. An overview of RNA virus-encoded micro RNAs. ExRNA 2019; 1: 37. doi:10.1186/s41544-019-0037-6.
  14. Frappier L. Regulation of herpesvirus reactivation by host microRNAs. J Virol 2015; 89(5): 2456-2458.
  15. Kincaid RP, Burke JM, Sullivan CS. RNA virus microRNA that mimics a B-cell oncomiR. Proc Natl Acad Sci USA 2012; 109(8): 3077-3082.
  16. Rosewick N, Momont M, Durkin K, et al. Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma. Proc Natl Acad Sci U S A 2013; 110(6): 2306-2311.
  17. Ceriani MC, Lendez PA, Martinez Cuesta L, et al. Bovine leukemia virus presence in breast tissue of Argentinian females and its association with cell proliferation and prognosis markers. Multidiscip Cancer Investig 2018; 2(4): 16-24.
  18. Frie MC, Droscha CJ, Greenlick AE, et al. MicroRNAs encoded by bovine leukemia virus (BLV) are associated with reduced expression of B cell transcriptional regulators in dairy cattle naturally infected with BLV. Front Vet Sci 2018; 4: 245. doi: 10.3389/fvets. 2017.00245.
  19. Ko M, An J, Pastor WA, et al. TET proteins and 5-methylcytosine oxidation in hematological cancers. Immunol Rev 2015; 263(1): 6-21.
  20. Kantidakis T, Saponaro M, Mitter R, et al. Mutation of cancer driver MLL2 results in transcription stress and genome instability. Genes Dev 2016; 30(4): 408-420.
  21. Hong CF, Lin SY, Chou YT, et al. MicroRNA-7 compromises p53 protein-dependent apoptosis by controlling the expression of the chromatin remodeling factor SMARCD1. J Biol Chem 2016; 291(4): 1877-1889.
  22. Zhan XY, Zhang Y, Zhai E, et al. Sorting nexin-1 is a candidate tumor suppressor and potential prognostic marker in gastric cancer. Peer J 2018; 6: e4829. doi:10.7717/peerj.4829.
  23. Qin L, Zhao J, Wu Y, et al. Association between insulin-like growth factor 1 gene rs35767 polymorphisms and cancer risk: A meta-analysis. Medicine (Baltimore) 2019; 98(46): e18017. doi: 10.1097/MD.00000000 00018017.
  24. Qin X, Li C, Guo T, et al. Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway. J Exp Clin Cancer Res 2017; 36(1): 148. doi: 10.1186/s13046-017-0618-x.
  25. Bjerre MT, Strand SH, Nørgaard M, et al. Aberrant DOCK2, GRASP, HIF3A and PKFP hypermethylation has potential as a prognostic biomarker for prostate cancer. Int J Mol Sci 2019; 20(5): 1173. doi: 10.3390/ ijms20051173.
  26. Vojtechova Z, Tachezy R. The role of miRNAs in virus-mediated oncogenesis. Int J Mol Sci 2018; 19(4): 1217. doi: 10.3390/ijms19041217.
  27. Yang Y, Chu S, Shang S, et al. Short communication: Genotyping and single nucleotide polymorphism analysis of bovine leukemia virus in Chinese dairy cattle. J Dairy Sci 2019; 102(4): 3469-3473.
  28. Aramburu J, López-Rodríguez C. Regulation of inflammatory functions of macrophages and T lymphocytes by NFAT5. Front Immunol 2019; 10: 535. doi: 10.3389/fimmu.2019.00535.
  29. Philippou A, Maridaki M, Pneumaticos S, et al. The complexity of the IGF1 gene splicing, posttranslational modification and bioactivity. Mol Med 2014; 20(1): 202-214.
  30. Zhu Y, Zhao H, Rao M, et al. MicroRNA-365 inhibits proliferation, migration and invasion of glioma by targeting PIK3R3. Oncol Rep 2017; 37(4): 2185-2192.
  31. Li W, Xu L. Epigenetic function of TET family, 5-methylcytosine, and 5-hydroxymethylcytosine in hematologic malignancies. Oncol Res Treat 2019; 42(6): 309-318.
  32. Olive V, Jiang I, He L. mir-17-92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol 2010; 42(8): 1348-1354.
  33. Kwon JJ, Factora TD, Dey S, et al. A systematic review of miR-29 in cancer. Mol Ther Oncolytics 2018;12:
    173-194.
  34. Alizadeh M, Safarzadeh A, Beyranvand F, et al. The potential role of miR‐29 in health and cancer diagnosis, prognosis, and therapy. J Cell Physiol 2019; 234(11): 19280-19297.
  35. Gillet NA, Hamaidia M, de Brogniez A, et al. Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo. PLoS Pathog 2016; 12(4): e1005588. doi: 10.1371/journal.ppat.1005588.
  36. Schwingel D, Andreolla AP, Erpen LMS, et al. Bovine leukemia virus DNA associated with breast cancer in women from South Brazil. Sci Rep 2019; 9(1): 2949. doi: 10.1038/s41598-019-39834-7.
Volume 13, Issue 2
June 2022
Pages 265-274
  • Receive Date: 04 April 2020
  • Revise Date: 12 August 2020
  • Accept Date: 07 September 2020
  • First Publish Date: 05 April 2022