Russian Journal of Genetics

, Volume 54, Issue 5, pp 568–575 | Cite as

MicroRNA Biogenesis Pathway Gene Polymorphisms Are Associated with Breast Cancer Risk

  • M. A. Bermisheva
  • Z. R. Takhirova
  • I. R. Gilyazova
  • E. K. Khusnutdinova
Human Genetics


MicroRNAs (miRNAs) play an important role as epigenetic regulators in cancer initiation and progression. One of the mechanisms of miRNA dysregulation is altered functioning of proteins involved in miRNA processing machinery. It has been suggested that single nucleotide polymorphisms (SNPs) within miRNA gene regions, miRNA target genes, and miRNA machinery genes may affect the miRNAs regulation. We selected 25 SNPs in the key genes of miRNA biosynthesis, including DROSHA/RNASEN, DGCR8, DICER1, XPO5, RAN, PIWIL1/HIWI, AGO1/EIF2C1, AGO2, GEMIN4, GEMIN3/DDX20, and DDX5, and investigated the association between these SNPs and the risk of breast cancer. The total number of breast cancer cases and cancer-free controls enrolled in the investigation were 778 (417 breast cancer patients and 361 healthy women). We found that rs11060845 and rs10773771 in the PIWIL1 gene, rs3809142/RAN, rs10719/DROSHA, rs1640299/DGCR8, rs563002/DDX20, rs595055/AGO1, and rs2740348/GEMIN4 were associated with breast cancer risk in Russians.


breast cancer miRNA association SNP disease risk 


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  1. 1.
    Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function, Cell, 2004, vol. 116, pp. 281–297.CrossRefPubMedGoogle Scholar
  2. 2.
    Catalanotto, C., Cogoni, C., and Zardo, G., MicroRNA in control of gene expression: an overview of nuclear functions, Int. J. Mol. Sci., 2016, vol. 17, p. 1712. doi 10.3390/ijms17101712CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Lee, Y., Ahn, Ch., and Han, J., The nuclear RNase III Drosha initiates microRNA processing, Nature, 2003, vol. 425, pp. 415–419.CrossRefPubMedGoogle Scholar
  4. 4.
    Kiselev, F.L., MicroRNA and cancer, Mol. Biol. (Moscow), 2014, vol. 48, pp. 232–242.Google Scholar
  5. 5.
    Loginov, V.I., Burdennyi, A. M., Pronina, I.V., et al., Novel miRNA genes hypermethylated in breast cancer, Mol. Biol. (Moscow), 2016, vol. 50, pp. 705–709. https://org/. doi 10.1134/S0026893316050101CrossRefGoogle Scholar
  6. 6.
    Lo, P.-K., Wolfson, B., Zhou, X., et al., Noncoding RNAs in breast cancer, Briefings Funct. Genomics, 2016, vol. 15, pp. 200–221.CrossRefGoogle Scholar
  7. 7.
    Sethupathy, P. and Collins, F.S., MicroRNA target site polymorphisms and human disease, Trends Genet., 2008, vol. 24, pp. 489–497.CrossRefPubMedGoogle Scholar
  8. 8.
    Hata, A. and Kashima, R., Dysregulation of microRNA biogenesis machinery in cancer, Crit. Rev. Biochem. Mol. Biol., 2016, vol. 51, pp. 121–134.CrossRefPubMedGoogle Scholar
  9. 9.
    Obsteter, J., Dovc, P., and Kunej, T., Genetic variability of microRNA regulome in human, Mol. Genet. Genomic Med., 2015, vol. 3, pp. 30–39.CrossRefPubMedGoogle Scholar
  10. 10.
    Mullany, L.E., Herrick, J.S., Wolff, R.K., et al., Impact of polymorphisms in microRNA biogenesis genes on colon cancer risk and microRNA expression levels: a population based, case-control study, BMC Med. Genomics, 2016, vol. 9, p. 21. doi 10.1186/s12920-016-0181-xCrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sun, G., Yan, J., Noltner, K., et al., SNPs in human miRNA genes affect biogenesis and function, RNA, 2009, vol. 15, pp. 1640–1651.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kim, J.S., Choi, Y.Y., Jin, G., et al., Association of a common AGO1 variant with lung cancer risk: a twostage case-control study, Mol. Carcinogen., 2010, vol. 49, pp. 913–921.CrossRefGoogle Scholar
  13. 13.
    Cho, S., Ko, J., Kim, J., et al., 3'-UTR polymorphisms in the miRNA machinery genes DROSHA, DICER1, RAN, and XPO5 are associated with colorectal cancer risk in a Korean population, PLoS One, 2015. doi 10.1371/journal.pone.0131125Google Scholar
  14. 14.
    Leaderer, D., Hoffman, A.E., Zheng, T., et al., Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis, Int. J. Mol. Epidemiol. Genet., 2011, vol. 2, pp. 9–18.PubMedGoogle Scholar
  15. 15.
    Jiang, Y., Chen, J., Wu, J., et al., Evaluation of genetic variants in microRNA biosynthesis genes and risk of breast cancer in Chinese women, Int. J. Cancer, 2013, vol. 133, pp. 2216–2224.CrossRefPubMedGoogle Scholar
  16. 16.
    Liang, D., Meyer, L., Chang, D.W., et al., Genetic variants in microRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response, Cancer Res., 2010, vol. 70, pp. 9765–9776.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sung, H., Lee, K.M., Choi, J.Y., et al., Common genetic polymorphisms of microRNA biogenesis pathway genes and risk of breast cancer: a case-control study in Korea, Breast Cancer Res. Treat., 2011, vol. 130, pp. 939–951.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhao, Y., Du, Y., Zhao, Sh., and Guo, Zh., Singlenucleotide polymorphisms of microRNA processing machinery genes and risk of colorectal cancer, Onco-Targets Ther., 2015, vol. 8, pp. 421–425.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Nikolić, Z., Pavicević, D., Vućić, N., et al., Genetic variants in RNA-induced silencing complex genes and prostate cancer, World J. Urol., 2016. doi 10.1007/s00345-016-1917-0Google Scholar
  20. 20.
    Iuliano, R., Vismara, M., Dattilo, V., et al., The role of microRNAs in cancer susceptibility, Biomed. Res. Int., 2013: 591931. doi 10.1155/2013/591931Google Scholar
  21. 21.
    Kumar, M.S., Lu, J., Mercer, K.L., et al., Impaired microRNA processing enhances cellular transformation and tumorigenesis, Nat. Genet., 2007, vol. 39, pp. 673–677.CrossRefPubMedGoogle Scholar
  22. 22.
    Gregory, R.I., Chendrimada, T.P., and Shiekhattar, R., MicroRNA biogenesis: isolation and characterization of the microprocessor complex, Meth. Mol. Biol., 2006, vol. 342, pp. 33–47.Google Scholar
  23. 23.
    Huang, J.-T., Wang, J., Srivastava, V., et al., MicroRNA machinery genes as novel biomarkers for cancer, Front. Oncol., 2014, vol. 4, p. 113.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Kwon, S., Lee, J., Kim, B., et al., Complexity in regulation of microRNA machinery components in invasive breast carcinoma, Pathol. Oncol. Res., 2014, vol. 20, pp. 697–705.CrossRefPubMedGoogle Scholar
  25. 25.
    Fardmanesh, H., Shekari, M., Movafagh, A., et al., Upregulation of the double-stranded RNA binding protein DGCR8 in invasive ductal breast carcinoma, Gene, 2016, vol. 581, pp. 146–151.CrossRefPubMedGoogle Scholar
  26. 26.
    Khan, S., Greco, D., Michailidou, K., et al., MicroRNA related polymorphisms and breast cancer risk, PLoS One, 2014, vol. 9: e109973. doi 10.1371/journal.pone.0109973CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Osuch-Wojcikiewicz, E., Bruzgielewicz, A., Niemczyk, K., et al., Association of polymorphic variants of miRNA processing genes with larynx cancer risk in a Polish population, Biomed. Res. Int., 2015. doi 10.1155/2015/298378Google Scholar
  28. 28.
    Li, Y., Kong, D., Ahmad, A., et al., Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion, Epigenetics, 2012, vol. 7, pp. 940–949.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hatakeyama, S., TRIM proteins and cancer. Nat. Rev. Cancer, 2011, vol. 11, pp. 792–804.CrossRefPubMedGoogle Scholar
  30. 30.
    Murchison, E.P. and Hannon, G.J., miRNAs on the move: miRNA biogenesis and the RNAi machinery, Curr. Opin. Cell Biol., 2004, vol. 16, pp. 223–229.CrossRefPubMedGoogle Scholar
  31. 31.
    Sorokin, A.V., Kim, E.R., and Ovchinnikov, L.P., Nuclear-cytoplasmic transport of proteins, Usp. Biol. Khim., 2007, vol. 47, pp. 89–128.Google Scholar
  32. 32.
    Finnegan, E.F. and Pasquinelli, A.E., MicroRNA biogenesis: regulating the regulators, Crit. Rev. Biochem. Mol. Biol., 2013, vol. 48, pp. 51–68.CrossRefPubMedGoogle Scholar
  33. 33.
    Clarke, P.R. and Zhang, C., Spatial and temporal coordination of mitosis by Ran GTPase, Nat. Rev. Mol. Cell Biol., 2008, vol. 9, pp. 464–477.CrossRefPubMedGoogle Scholar
  34. 34.
    Rensen, W.M., Mangiacasale, R., Ciciarello, M., and Lavia, P., The GTPase Ran: regulation of cell life and potential roles in cell transformation, Front. Biosci., 2008, vol. 13, pp. 4097–4121.CrossRefPubMedGoogle Scholar
  35. 35.
    Xia, F., Lee, C., and Altieri, D., Tumor cell dependence on Ran-GTP-directed mitosis, Cancer Res., 2008, vol. 68, pp. 1826–1833.CrossRefPubMedGoogle Scholar
  36. 36.
    Ly, T.K., Wang, J., Pereira, R., et al., Activation of the Ran GTPase is subject to growth factor regulation and can give rise to cellular transformation, J. Biol. Chem., 2010, vol. 285, pp. 5815–5826.CrossRefPubMedGoogle Scholar
  37. 37.
    Yuen, H.F., Chan, K.K., Grills, C., et al., Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways, Clin. Cancer Res., 2012, vol. 18, pp. 380–391.CrossRefPubMedGoogle Scholar
  38. 38.
    Woo, I.S., Jang, H.S., Eun, S.Y., et al., Ran suppresses paclitaxel-induced apoptosis in human glioblastoma cells, Apoptosis, 2008, vol. 13, pp. 1223–1231.CrossRefPubMedGoogle Scholar
  39. 39.
    Honma, K., Takemasa, I., Matoba, R., et al., Screening of potential molecular targets for colorectal cancer therapy, Int. J. Gen. Med., 2009, vol. 2, pp. 243–257.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Xie, Y., Wang, Y., Zhao, Y., and Guo, Zh., Singlenucleotide polymorphisms of microRNA processing machinery genes are associated with risk for gastric cancer, OncoTargets Ther., 2015, vol. 8, pp. 567–571.Google Scholar
  41. 41.
    Kim, M., Kim, J., Lee, S., et al., Variation in the dicer and RAN genes are associated with survival in patients with hepatocellular carcinoma, PLoS One, 2016, vol. 11, no. 9. doi 10.1371/journal.pone.0162279Google Scholar
  42. 42.
    Sasaki, T., Shiohama, A., Minoshima, S., and Shimizu, N., Identification of eight members of the Argonaute family in the human genome, Genomics, 2003, vol. 82, pp. 323–330.CrossRefPubMedGoogle Scholar
  43. 43.
    Ng, K.W., Anderson, C., Marshall, E.A., et al., Piwi interacting RNAs in cancer: emerging functions and clinical utility, Mol. Cancer, 2016, vol. 15, pp. 1–13.CrossRefGoogle Scholar
  44. 44.
    Suzuki, R., Honda, S., Kirino, Y., et al., PIWI expression and function in cancer, Front. Genet., 2012, vol. 3, p. 204.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Krishnan, P., Ghosh, S., Graham, K., et al., Piwiinteracting RNAs and PIWI genes as novel prognostic markers for breast cancer, Oncotarget, 2016, vol. 7, pp. 37944–37956.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Iliev, R., Fedorko, M., Machackova, T., et al., Expression levels of PIWI-interacting RNA, piR-823, are deregulated in tumor tissue, blood serum and urine of patients with renal cell carcinoma, Anticancer Res., 2016, vol. 36, pp. 6419–6423.CrossRefPubMedGoogle Scholar
  47. 47.
    Hashim, A., Rizzo, F., Marchese, G., et al., RNA sequencing identifies specific PIWI-interacting small non-coding RNA expression patterns in breast cancer, Oncotarget, 2014, vol. 5, pp. 9901–9910.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Paris, O., Ferraro, L., Grober, O.M., et al., Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer. Oncogene, 2012, vol. 31, pp. 4196–4206.CrossRefPubMedGoogle Scholar
  49. 49.
    Wang, D.-W., Wang, Zh.-H., Wang, L.-L., et al., Overexpression of hiwi promotes growth of human breast cancer cells, Asian Pac. J. Cancer Prev., 2014, vol. 15, pp. 7553–7558.CrossRefPubMedGoogle Scholar
  50. 50.
    Sung, H., Jeon, S., Lee, K.-M., et al., Common genetic polymorphisms of microRNA biogenesis pathway genes and breast cancer survival, BMC Cancer, 2012, vol. 12, p. 195.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ma, H., Yuan, H., Yuan, Z., et al., Genetic variations in key microRNA processing genes and risk of head and neck cancer: a case-control study in Chinese population, PLoS One, 2012, vol. 7: e47544. doi 10.1371/journal. pone.0047544CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Fu, L., Li, Z.H., Zhu, J., et al., Serum expression levels of microRNA-382-3p,-598-3p,-1246 and-184 in breast cancer patients, Oncol. Lett., 2016, vol. 12, pp. 269–274.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Zhu, J., Zheng, Zh., Wang, J., et al., Different miRNA expression profiles between human breast cancer tumors and serum, Front. Genet., 2014, vol. 5, p. 149.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Mohammadi-Yeganeh, S., Paryan, M., Arefian, E., et al., MicroRNA-340 inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway, Tumour Biol., 2016, vol. 37, pp. 8993–9000.CrossRefPubMedGoogle Scholar
  55. 55.
    Valdmanis, P.N., Gu, Sh., Schurmann, N., et al., Expression determinants of mammalian argonaute proteins in mediating gene silencing, Nucleic Acids Res., 2012, vol. 40, pp. 3704–3713.CrossRefPubMedGoogle Scholar
  56. 56.
    Davis-Dusenbery, B.N. and Hata, A., Mechanisms of control of microRNA biogenesis, J. Biochem., 2010, vol. 148, pp. 381–392.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Cheng, C., Fu, X., Alves, P., and Gerstein, M., mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer, Genome Biol., 2009. doi 10.1186/gb-2009-10-9-r90Google Scholar
  58. 58.
    Mourelatos, Z., Dostie, J., Paushkin, S., et al., miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs, Genes Dev., 2002, vol. 16, pp. 720–728.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Roy, R., De Sarkar, N., Ghose, S., et al., Association between risk of oral precancer and genetic variations in microRNA and related processing genes, J. Biomed. Sci., 2014, vol. 21, p. 48.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ke, H.-L., Chen, M., Ye, Y., et al., Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer, Carcinogenesis, 2013, vol. 34, pp. 1006–1011.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gao, Y., Diao, L., Li, H., and Guo, Zh., Single nucleotide polymorphisms of microRNA processing genes and outcome of non-Hodgkin’s lymphoma, OncoTargets Ther., 2015, vol. 8, pp. 1735–1741.CrossRefGoogle Scholar
  62. 62.
    Yang, H., Dinney, C.P., Ye, Y., et al., Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer, Cancer Res., 2008, vol. 68, pp. 2530–2537.CrossRefPubMedGoogle Scholar
  63. 63.
    Horikawa, Y., Wood, C.G., Yang, H., et al., Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma, Clin. Cancer Res., 2008, vol. 14, pp. 7956–7962.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhu, W., Zhao, J., He, J., et al., Genetic variants in the microRNA biosynthetic pathway Gemin3 and Gemin4 are associated with a risk of cancer: a meta-analysis, PeerJ., 2016. doi 10.7717/peerj.1724Google Scholar
  65. 65.
    Liu, J., Liu, J., Wei, M., et al., Genetic variants in the microRNA machinery gene GEMIN4 are associated with risk of prostate cancer: a case-control study of the Chinese Han population, DNA Cell Biol., 2012, vol. 31, pp. 1296–1302.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • M. A. Bermisheva
    • 1
  • Z. R. Takhirova
    • 1
  • I. R. Gilyazova
    • 1
  • E. K. Khusnutdinova
    • 1
    • 2
  1. 1.Institute of Biochemistry and Genetics, Ufa Science CenterRussian Academy of SciencesUfaRussia
  2. 2.Department of Genetics and Fundamental MedicineBashkir State UniversityUfaRussia

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