Document Type : Original Research
Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Department of Laboratory Sciences, School of Allied Health Sciences, Ahvaz Jundishapur University of Medical sciences Ahvaz, Iran
Department of Microbiology, Shahid Sadoghi University of Medical Sciences, Yazd, Iran
Department of Nuclear Medicine, School of Medicine, Golestan Hospital, Ahvaz Jundishapur University of Medical sciences, Ahvaz, Iran
Background & Objective: The role of Epstein-Barr Virus in development of breast cancer is frequently studied. In this regard, miRNAs are among the contributing elements in the molecular pathophysiology of EBV-related diseases. In addition, a growing number of host miRNAs are believed to be implicated in pathogenesis of breast cancer. MiR-218 is a tumor suppressive miRNA that is subjected to dysregulation in various EBV-associated cancers. We aimed to investigate the frequency of EBV and its relationship with expression status of tumor suppressive miR-218 in breast cancer and adjacent normal tissue.
Methods: A total number of 51 fresh malignant breast cancer tissues (cases) and their adjacent normal tissues (controls) were collected. Nested-PCR and RT-qPCR were set to identify EBV frequency and miR-218 expression in cases and controls, respectively.
Results: Out of all samples, 6.8% (7/102) comprising 11.6% (6/51) in malignant tissues and 1.9% (1/51) in normal control tissues were positive for EBV (P<0.05). Quantitative data showed that miR-218 was significantly downregulated in malignant tissues compared to control tissues (P<0.0001). In addition, reduced expression of miR-218 was associated with adverse clinical outcomes, metastasis, and higher grades of malignancy. Given the presence of EBV, lower expression of miR-218 was observed in breast cancer group in comparison with normal group (P<0.05).
Conclusion: Our results raise the possibility of the relation between EBV infection and miR-218 downregulation in breast cancer and propose further investigations in this regard.
Copyright © 2021. This is an open-access article distributed under the terms of the Creative Commons Attribution- 4.0 International License which permits Share, copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, even commercially.
- Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer (Dove Med Press). 2019;11:151-64. [DOI:10.2147/BCTT.S176070] [PMID] [PMCID]
- Ataollahi MR, Sharifi J, Paknahad MR, Paknahad A. Breast cancer and associated factors: a review. J Med Life. 2015;8(Spec Iss 4):6-11.
- Alibek K, Kakpenova A, Mussabekova A, Sypabekova M, Karatayeva N. Role of viruses in the development of breast cancer. Infect Agent Cancer. 2013;8(1):32. [DOI:10.1186/1750-9378-8-32] [PMID] [PMCID]
- Farahmand M, Monavari SH, Shoja Z, Ghaffari H, Tavakoli M, Tavakoli A. Epstein-Barr virus and risk of breast cancer: a systematic review and meta-analysis. Future Oncol. 2019;15(24):2873-85. [DOI:10.2217/fon-2019-0232] [PMID]
- Kuri A, Jacobs BM, Vickaryous N, Pakpoor J, Middeldorp J, Giovannoni G, et al. Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom. BMC Public Health. 2020;20(1):912. [DOI:10.1186/s12889-020-09049-x] [PMID] [PMCID]
- Bakkalci D, Jia Y, Winter JR, Lewis JE, Taylor GS, Stagg HR. Risk factors for Epstein Barr virus-associated cancers: a systematic review, critical appraisal, and mapping of the epidemiological evidence. J Glob Health. 2020;10(1):010405. [DOI:10.7189/jogh.10.010405] [PMID] [PMCID]
- Charostad J, Astani A, Goudarzi H, Faghihloo E. DNA methyltransferases in virus-associated cancers. Rev Med Virol. 2019;29(2):e2022. [DOI:10.1002/rmv.2022] [PMID]
- Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein-Barr virus in epithelial malignancies. J Pathol. 2015;235(2):323-33. [DOI:10.1002/path.4448] [PMID] [PMCID]
- Ayee R, Ofori MEO, Wright E, Quaye O. Epstein Barr Virus Associated Lymphomas and Epithelia Cancers in Humans. J Cancer. 2020;11(7):1737-50. [DOI:10.7150/jca.37282] [PMID] [PMCID]
- Hippocrate A, Oussaief L, Joab I. Possible role of EBV in breast cancer and other unusually EBV-associated cancers. Cancer Lett. 2011;305(2):144-9. [DOI:10.1016/j.canlet.2010.11.007] [PMID]
- Charostad J, Nakhaie M, Dehghani A, Faghihloo E. The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis. Infectious Agents and Cancer. 2020;15(1):1-12. [DOI:10.1186/s13027-020-00317-4] [PMID] [PMCID]
- Arbach H, Viglasky V, Lefeu F, Guinebretiere JM, Ramirez V, Bride N, et al. Epstein-Barr virus (EBV) genome and expression in breast cancer tissue: effect of EBV infection of breast cancer cells on resistance to paclitaxel (Taxol). J Virol. 2006;80(2):845-53. [DOI:10.1128/JVI.80.2.845-853.2006] [PMID] [PMCID]
- Shahriar A, Ghaleh-Aziz Shiva G, Ghader B, Farhad J, Hosein A, Parsa H. The dual role of mir-146a in metastasis and disease progression. Biomed Pharmacother. 2020;126:110099. [DOI:10.1016/j.biopha.2020.110099] [PMID]
- Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem. 2017;8(1):45-56. [DOI:10.4331/wjbc.v8.i1.45] [PMID] [PMCID]
- Loh HY, Norman BP, Lai KS, Rahman N, Alitheen NBM, Osman MA. The Regulatory Role of MicroRNAs in Breast Cancer. Int J Mol Sci. 2019;20(19):4940. [DOI:10.3390/ijms20194940] [PMID] [PMCID]
- Hassani A, Khan G. Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis? Front Immunol. 2019;10:695. [DOI:10.3389/fimmu.2019.00695] [PMID] [PMCID]
- Iizasa H, Kim H, Kartika AV, Kanehiro Y, Yoshiyama H. Corrigendum: Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases. Front Immunol. 2020;11:498. [DOI:10.3389/fimmu.2020.00498] [PMID] [PMCID]
- Svoronos AA, Engelman DM, Slack FJ. OncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer. Cancer Res. 2016;76(13):3666-70. [DOI:10.1158/0008-5472.CAN-16-0359] [PMID] [PMCID]
- Yang Y, Ding L, Hu Q, Xia J, Sun J, Wang X, et al. MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL-6/STAT3 and negatively correlates with poor prognosis. Molecular cancer. 2017;16(1):141. [DOI:10.1186/s12943-017-0710-z] [PMID] [PMCID]
- Lu YF, Zhang L, Waye MM, Fu WM, Zhang JF. MiR-218 mediates tumorigenesis and metastasis: Perspectives and implications. Exp Cell Res. 2015;334(1):173-82. [DOI:10.1016/j.yexcr.2015.03.027] [PMID]
- Ghosh Z, Mallick B, Chakrabarti J. Cellular versus viral microRNAs in host-virus interaction. Nucleic Acids Res. 2009;37(4):1035-48. [DOI:10.1093/nar/gkn1004] [PMID] [PMCID]
- Alajez NM, Lenarduzzi M, Ito E, Hui AB, Shi W, Bruce J, et al. MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer research. 2011;71(6):2381-91. [DOI:10.1158/0008-5472.CAN-10-2754] [PMID]
- Motsch N, Alles J, Imig J, Zhu J, Barth S, Reineke T, et al. MicroRNA profiling of Epstein-Barr virus-associated NK/T-cell lymphomas by deep sequencing. PLoS One. 2012;7(8):e42193. [DOI:10.1371/journal.pone.0042193] [PMID] [PMCID]
- Kim M, Kim JH, Baek SJ, Kim SY, Kim YS. Specific expression and methylation of SLIT1, SLIT2, SLIT3, and miR-218 in gastric cancer subtypes. Int J Oncol. 2016;48(6):2497-507. [DOI:10.3892/ijo.2016.3473] [PMID]
- Glaser SL, Hsu JL, Gulley ML. Epstein-Barr virus and breast cancer: state of the evidence for viral carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2004;13(5):688-97.
- Vojtechova Z, Tachezy R. The Role of miRNAs in Virus-Mediated Oncogenesis. Int J Mol Sci. 2018;19(4):1217. [DOI:10.3390/ijms19041217] [PMID] [PMCID]
- Labrecque LG, Barnes DM, Fentiman IS, Griffin BE. Epstein-Barr virus in epithelial cell tumors: a breast cancer study. Cancer Res. 1995;55(1):39-45.
- Kazemi Aghdam M, Nadji SA, Khoddami M, Baghizadeh Dezfuli H, Khademi Y. Epstein-Barr Virus and breast carcinoma in Iran. Jundishapur Journal of Microbiology. 2017;10(10). [DOI:10.5812/jjm.12800]
- Reza MA, Reza MH, Mahdiyeh L, Mehdi F, Hamid ZN. Evaluation Frequency of Merkel Cell Polyoma, Epstein-Barr and Mouse Mammary Tumor Viruses in Patients with Breast Cancer in Kerman, Southeast of Iran. Asian Pac J Cancer Prev. 2015;16(16):7351-7. [DOI:10.7314/APJCP.2015.16.16.7351] [PMID]
- Saeedi Z, Hadi F, Hejazi SH, Salahshournia Z. The relationship between EBV virus and breast cancer in Khuzestan province of Iran. Journal of Applied Biotechnology Reports. 2018;5(1):37-41. [DOI:10.29252/JABR.01.01.07]
- Antonsson A, Bialasiewicz S, Rockett RJ, Jacob K, Bennett IC, Sloots TP. Exploring the prevalence of ten polyomaviruses and two herpes viruses in breast cancer. PLoS One. 2012;7(8):e39842. [DOI:10.1371/journal.pone.0039842] [PMID] [PMCID]
- Ladera M, Fernandes A, López M, Pesci-Feltri A, Ávila M, Correnti M. Presence of human papillomavirus and Epstein-Barr virus in breast cancer biopsies as potential risk factors. Gaceta Mexicana de Oncologia. 2017;16(2):103-8. [DOI:10.24875/j.gamo.17000018]
- Liu B, Tian Y, Li F, Zhao Z, Jiang X, Zhai C, et al. Tumor-suppressing roles of miR-214 and miR-218 in breast cancer. Oncol Rep. 2016;35(6):3178-84. [DOI:10.3892/or.2016.4749] [PMID] [PMCID]
- Ahmadinejad F, Mowla SJ, Honardoost M-A, Arjenaki MG, Moazeni-Bistgani M, Kheiri S, et al. Lower expression of miR-218 in human breast cancer is associated with lymph node metastases, higher grades, and poorer prognosis. Tumor Biology. 2017;39(8):1010428317698362. [DOI:10.1177/1010428317698362] [PMID]
- Gao L, Ai J, Xie Z, Zhou C, Liu C, Zhang H, et al. Dynamic expression of viral and cellular microRNAs in infectious mononucleosis caused by primary Epstein-Barr virus infection in children. Virol J. 2015;12(1):208. [DOI:10.1186/s12985-015-0441-y] [PMID] [PMCID]