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Methylation profile of group of miRNA genes in clear cell renal cell carcinoma and their involvement in cancer progression

  • Human Genetics
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Abstract

MicroRNA regulates gene expression, is involved in many cellular processes, and plays an important role in the development of cancer. The regulation of the expression of miRNA genes can be achieved by methylating their CpG islands, which is shown in different types of tumors. The methylation of miRNA genes in clear cell renal cell carcinoma (CCRCC) has mainly been studied for the miR-9 and miR-34 families. The methylation of six miRNA genes (miR-124a-2, -124a-3, -9-1, -9-3, -34b/c, -129-2) was analyzed with using a representative sample (46 cases). Methylation of three genes miR -124a-2, -124a-3, and -129-2 was studied in kidney tumors for the first time. Methylation analysis was performed using methyl specific PCR. It is shown that the frequency of methylation of six genes was changed from 37% to 65% in tumor samples and significantly higher in tumor samples than in samples of histologically normal tissue (P ≤ 3 × 10−5 by Fisher’s exact test). These results suggest the properties of tumor suppressors for the six miRNA genes indicated in CCRCC. We also found correlations between the methylation frequency of some miRNA genes and signs of the progression of CCRCC (tumor size, clinical stage, loss of differentiation, and metastasis).

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References

  1. Janga, S.C. and Vallabhaneni, S., MicroRNAs as Post-Transcriptional Machines and Their Interplay with Cellular Networks, Adv. Exp. Med. Biol., 2011, vol. 722, pp. 59–74.

    Article  PubMed  CAS  Google Scholar 

  2. Munker, R. and Calin, G.A., MicroRNA Profiling in Cancer, Clin. Sci., (London), 2011, vol. 121, no. 4, pp. 141–158.

    Article  CAS  Google Scholar 

  3. Han, L., Witmer, P.D., Casey, E., et al., DNA Methylation Regulates MicroRNA Expression, Cancer Biol. Ther., 2007, vol. 6, no. 8, pp. 1284–1288.

    PubMed  CAS  Google Scholar 

  4. Lujambio, A., Calin, G.A., Villanueva, A., et al., A MicroRNA DNA Methylation Signature for Human Cancer Metastasis, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 36, pp. 13556–13561.

    Article  PubMed  CAS  Google Scholar 

  5. Sato, F., Tsuchiya, S., Meltzer, S.J., and Shimizu, K., MicroRNAs and Epigenetics, FEBS J., 2011, vol. 278, no. 10, pp. 1598–1609.

    Article  PubMed  CAS  Google Scholar 

  6. Jermal, A., Siegel, R., Ward, E., et al., Cancer Statistics, Ca-Cancer J. Clin., 2009, vol. 59, no. 4, pp. 225–249.

    Article  Google Scholar 

  7. Chissov, V.I., Starinskii, V.V., and Petrova, G.V., Zlokachestvennye novoobrazovaniya v Rossii v 2010 godu (zabolevaemost’ i smertnost’) (Malignant Neoplasms in Russia 2010 (Morbidity and Mortality)), Moscow: Mosk. nauch. issl. onkol. inst. im. P.A. Gertsena, 2012.

    Google Scholar 

  8. Rini, B.I., Campbell, S.C., and Escudier, B., Renal Cell Carcinoma, Lancet, 2009, vol. 373, no. 9669, pp. 1119–1132.

    Article  PubMed  CAS  Google Scholar 

  9. Hildebrandt, M.A., Gu, J., Lin, J., et al., Hsa-miR-9 Methylation Status Is Associated with Cancer Development and Metastatic Recurrence in Patients with Clear Cell Renal Cell Carcinoma, Oncogene, 2010, vol. 29, no. 42, pp. 5724–5728.

    Article  PubMed  CAS  Google Scholar 

  10. Redova, M., Svoboda, M., and Slaby, O., MicroRNAs and Their Target Gene Networks in Renal Cell Carcinoma, Biochem. Biophys. Res. Commun., 2011, vol. 405, no. 2, pp. 153–156.

    Article  PubMed  CAS  Google Scholar 

  11. Jung, M., Mollenkopf, H.J., Grimm, C., et al., MicroRNA Profiling of Clear Cell Renal Cell Cancer Identifies a Robust Signature to Define Renal Malignancy, J. Cell. Mol. Med., 2009, vol. 13, pp. 3918–3928.

    Article  PubMed  Google Scholar 

  12. Heinzelmann, J., Henning, B., Sanjmyatav, J., et al., Specific miRNA Signatures Are Associated with Metastasis and Poor Prognosis in Clear Cell Renal Cell Carcinoma, World J. Urol., 2011, vol. 29, no. 3, pp. 367–373.

    Article  PubMed  CAS  Google Scholar 

  13. Neal, C.S., Michael, M.Z., Rawlings, L.H., et al., The VHL-Dependent Regulation of MicroRNAs in Renal Cancer, BMC Med., 2010, vol. 8, no. 64.

    Google Scholar 

  14. Vogt, M., Munding, J., Grüner, M., et al., Frequent Concomitant Inactivation of miR-34a and miR-34b/c by CpG Methylation in Colorectal, Pancreatic, Mammary, Ovarian, Urothelial, and Renal Cell Carcinomas and Soft Tissue Sarcomas, Virchows Arch., 2011, vol. 458, no. 3, pp. 313–322.

    Article  PubMed  Google Scholar 

  15. UICC TNM Classification of Malignant Tumors, Sobin, L.Y. and Wittekind, Ch., Eds., New York: Wiley-Liss, 2002, 6th ed.

    Google Scholar 

  16. World Health Organization: Classification of Tumors. Pathology and Genetics. Tumors of the Urinary System and Male Genital Organs, Eble, J.N., Sauter, G.S., Epsten, J.I., and Sisterhenn, I.A., Eds., Lyon: IARC Press, 2004.

    Google Scholar 

  17. Loginov, V.I., Malyukova, A.V., Seregin, Yu.A., et al., RASSF1A Gene Methylation Level in Renal, Breast, and Ovary Tumors, Mol. Biol. (Moscow), 2004, vol. 38, no. 4, pp. 654–667.

    Article  CAS  Google Scholar 

  18. Herman, J.G., Graff, J.R., Myohanen, S., et al., Methylation-Specific PCR: A Novel PCR Assay for Methylation Status of CpG Islands, Proc. Natl. Acad. Sci. U.S.A., 1996, vol. 93, no. 18, pp. 9821–9826.

    Article  PubMed  CAS  Google Scholar 

  19. Ando, T., Yoshida, T., Enomoto, S., et al., DNA Methylation of MicroRNA Genes in Gastric Mucosae of Gastric Cancer Patients: Its Possible Involvement in the Formation of Epigenetic Field Defect, Int. J. Cancer, 2009, vol. 124, no. 10, pp. 2367–2374.

    Article  PubMed  CAS  Google Scholar 

  20. Bandres, E., Agirre, X., Bitarte, N., et al., Epigenetic Regulation of MicroRNA Expression in Colorectal Cancer, Int. J. Cancer, 2009, vol. 125, no. 11, pp. 2737–2743.

    Article  PubMed  CAS  Google Scholar 

  21. Andorfer, C.A., Necela, B.M., Thompson, E.A., and Perez, E.A., MicroRNA Signatures: Clinical Biomarkers for the Diagnosis and Treatment of Breast Cancer, Trends Mol. Med., 2011, vol. 17, no. 6, pp. 313–319.

    Article  PubMed  CAS  Google Scholar 

  22. Youssef, Y.M., White, N.M., Grigull, J., et al., Accurate Molecular Classification of Kidney Cancer Subtypes Using MicroRNA Signature, Eur. Urol., 2011, vol. 59, no. 5, pp. 721–730.

    Article  PubMed  CAS  Google Scholar 

  23. Furuta, M., Kozaki, K.I., and Tanaka, S., miR-124 and miR-203 Are Epigenetically Silenced Tumor-Suppressive MicroRNAs in Hepatocellular Carcinoma, Carcinogenesis, 2010, vol. 31, no. 5, pp. 766–776.

    Article  PubMed  CAS  Google Scholar 

  24. Wilting, S.M., van Boerdonk, R.A., and Henken, F.E., Methylation-Mediated Silencing and Tumor Suppressive Function of hsa-miR-124 in Cervical Cancer, Mol. Cancer, 2010, vol. 9, no. 167.

    Google Scholar 

  25. Chen, X., Hu, H., Guan, X., et al., CpG Island Methylation Status of miRNAs in Esophageal Squamous Cell Carcinoma, Int. J. Cancer, 2012, vol. 130, no. 7, pp. 1607–1613.

    Article  PubMed  CAS  Google Scholar 

  26. Esquela-Kerscher, A. and Slack, F.J., Oncomirs—MicroRNAs with a Role in Cancer, Nat. Rev. Cancer, 2006, vol. 6, no. 4, pp. 259–269.

    Article  PubMed  CAS  Google Scholar 

  27. Lujambio, A. and Esteller, M., CpG Island Hypermethylation of Tumor Suppressor MicroRNAs in Human Cancer, Cell Cycle, 2007, vol. 6, no. 12, pp. 1455–1459.

    Article  PubMed  CAS  Google Scholar 

  28. Dreijerink, K., Braga, E., Kuzmin, I., et al., The Candidate Tumor Suppressor Gene, RASSF1A, from Human Chromosome 3p21.3 Is Involved in Kidney Tumorigenesis, Proc. Natl. Acad. Sci. U.S.A., 2001, vol. 98, no. 13, pp. 7504–7509.

    Article  PubMed  CAS  Google Scholar 

  29. Loginov, V.I., Khodyrev, D.S., Pronina, I.V., et al., Two CpG Islands in the Sema3B Gene: Methylation in Clear Cell Renal Cell Carcinoma, Mol. Biol. (Moscow), 2009, vol. 43, no. 6, pp. 1014–1018.

    Article  CAS  Google Scholar 

  30. Toyota, M., Suzuki, H., Sasaki, Y., and Maruyama, R., Epigenetic Silencing of MicroRNA-34b/c and B-Cell Translocation Gene 4 Is Associated with CpG Island Methylation in Colorectal Cancer, Cancer Res., 2008, vol. 68, no. 11, pp. 4123–4132.

    Article  PubMed  CAS  Google Scholar 

  31. Hermeking, H., The miR-34 Family in Cancer and Apoptosis, Cell Death. Differ., 2010, vol. 17, no. 2, pp. 193–199.

    Article  PubMed  CAS  Google Scholar 

  32. Katada, T., Ishiguro, H., Kuwabara, Y., et al., MicroRNA Expression Profile in Undifferentiated Gastric Cancer, Int. J. Oncol., 2009, vol. 34, no. 2, pp. 537–542.

    PubMed  CAS  Google Scholar 

  33. Wu, J., Qian, J., Li, C., et al., miR-129 Regulates Cell Proliferation by Downregulating Cdk6 Expression, Cell Cycle, 2010, vol. 9, no. 9, pp. 1809–1818.

    Article  PubMed  CAS  Google Scholar 

  34. Huang, Y.W., Liu, J.C., Deatherage, D.E., et al., Epigenetic Repression of MicroRNA-129-2 Leads to Overexpression of SOX4 Oncogene in Endometrial Cancer, Cancer Res., 2009, vol. 69, no. 23, pp. 9038–9046.

    Article  PubMed  CAS  Google Scholar 

  35. Wan, H.Y., Guo, L.M., Liu, T., et al., Regulation of the Transcription Factor NF-KappaB1 by MicroRNA-9 in Human Gastric Adenocarcinoma, Mol. Cancer, 2010, vol. 9, no. 16.

    Google Scholar 

  36. Rotkrua, P., Akiyama, Y., Hashimoto, Y., et al., miR-9 Down-Regulates CDX2 Expression in Gastric Cancer Cells, Int. J. Cancer, 2011, vol. 129, no. 11, pp. 2611–2620.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. State Research Institute of Genetics and Selection of Industrial Microorganisms, Moscow, 117545, Russia

    E. V. Beresneva, S. V. Rykov, D. S. Khodyrev, I. V. Pronina, E. A. Braga & V. I. Loginov

  2. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia

    V. D. Ermilova & T. P. Kazubskaya

  3. Medical Genetic Research Center, Russian Academy of Medical Sciences, Moscow, 115478, Russia

    E. A. Braga & V. I. Loginov

Authors
  1. E. V. Beresneva
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  2. S. V. Rykov
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  3. D. S. Khodyrev
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  4. I. V. Pronina
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  5. V. D. Ermilova
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  6. T. P. Kazubskaya
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  7. E. A. Braga
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  8. V. I. Loginov
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Correspondence to E. V. Beresneva.

Additional information

Original Russian Text © E.V. Beresneva, S.V. Rykov, D.S. Khodyrev, I.V. Pronina, V.D. Ermilova, T.P. Kazubskaya, E.A. Braga, V.I. Loginov, 2013, published in Genetika, 2013, Vol. 49, No. 3, pp. 366–375.

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Beresneva, E.V., Rykov, S.V., Khodyrev, D.S. et al. Methylation profile of group of miRNA genes in clear cell renal cell carcinoma and their involvement in cancer progression. Russ J Genet 49, 320–328 (2013). https://doi.org/10.1134/S1022795413030034

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  • DOI: https://doi.org/10.1134/S1022795413030034

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