Abstract
MicroRNAs play an important role in the regulation of expression of many genes and are involved in carcinogenesis. The regulation of miRNA gene expression can involve the methylation of promoter CpG islands. In this work, the methylation of six miRNA genes (mir-107, mir-125b-1, mir-130b, mir-137, mir-375, and mir-1258) in non-small-cell lung cancer (NSCLC) was studied for the first time by methylation-specific PCR using a representative set of specimens (39 cases). Four new genes (mir-125b-1, mir-137, mir-375, and mir-1258) methylated in primary NSCLC tumors were identified with frequencies of 56, 31, 56, and 36%, respectively. The frequencies of miRNA promoter methylation in DNA of tumors and histologically normal tissues differed significantly (P ≤ 0.05 by Fisher’s test). In lung tissues of 20 donors without a history of cancer, these genes were only methylated in a few cases. It was also shown that the previously unstudied promoter CpG islands of mir-107 and mir-130b were not methylated in NSCLC. The frequencies of mir-125b-1 and mir-137 methylation were shown for the first time to correlate with NSCLC progression (clinical stage and metastasis).
References
Mukeriya, A.F. and Zaridze, D.G., Epidemiology and prophylaxis of lung cancer, Vestn. Ross. Oncol. Nauchn. Tsentr im. N.N. Blokhina Ross. Akad. Med. Nauk, 2010, vol. 21, no. 3, pp. 3–12.
Jones, P.A., Functions of DNA methylation: islands, start sites, gene bodies and beyond, Nat. Rev. Genet., 2012, vol. 13, no. 7, pp. 484–492.
Kato, M. and Slack, F.J., microRNAs: small molecules with big roles—C. elegans to human cancer, Biol. Cell, 2008, vol. 100, no. 2, pp. 71–81.
Kunej, T., Godnic, I., Ferdin, J., et al., Epigenetic regulation of microRNAs in cancer: an integrated review of literature, Mutat. Res., 2011, vol. 717, nos. 1–2, pp. 77–84.
Qi, J. and Mu, D., microRNAs and lung cancers: from pathogenesis to clinical implications, Front. Med., 2012, vol. 6, no. 2, pp. 134–155.
Sato, F., Tsuchiya, S., Meltzer, S.J., et al., microRNAs and epigenetics, FEBS J., 2011, vol. 278, no. 10, pp. 1598–1609.
Khodyrev, D.S., Pronina, I.V., and Rykov, S.V., et al., Involvement of methylation of group of miRNA genes in regulation of expression of RAR-beta2 and NKIRAS1 target genes in lung cancer, Mol. Biol. (Moscow), 2012, vol. 46, no. 5, pp. 693–704.
Lee, K.H., Lotterman, C., Karikari, C., et al., Epigenetic silencing of microRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer, Pancreatology, 2009, vol. 9, no. 3, pp. 293–301.
Soto-Reyes, E., González-Barrios, R., Cisneros-Soberanis, F., et al., Disruption of CTCF at the miR-125b1 locus in gynecological cancers, BMC Cancer, 2012, vol. 12, no. 40.
Yang, C., Cai, J., Wang, Q., et al., Epigenetic silencing of miR-130b in ovarian cancer promotes the development of multidrug resistance by targeting colony-stimulating factor 1, Gynecol. Oncol., 2012, vol. 124, no. 2, pp. 325–334.
Balaguer, F., Link, A., Lozano, J.J., et al., Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis, Cancer Res., 2010, vol. 70, no. 16, pp. 6609–6618.
Zhang, Y., Yan, L.X., Wu, Q.N., et al., miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer, Cancer Res., 2011, vol. 71, no. 10, pp. 3552–3562.
Liu, H., Chen, X., Gao, W., et al., The expression of heparanase and microRNA-1258 in human non-small cell lung cancer, Tumour Biol., 2012, vol. 33, no. 5, pp. 1327–1334.
Zhang, L., Sullivan, P.S., Goodman, J.C., et al., microRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase, Cancer Res., 2011, vol. 71, no. 3, pp. 645–654.
Dacic, S., Kelly, L., Shuai, Y., et al., miRNA expression profiling of lung adenocarcinomas: correlation with mutational status, Mod. Pathol., 2010, vol. 23, no. 12, pp. 1577–1582.
Zhu, X., Li, Y., Shen, H., et al., miR-137 inhibits the proliferation of lung cancer cells by targeting Cdc42 and Cdk6, FEBS Lett., 2013, vol. 587, no. 1, pp. 73–81.
Friboulet, L., Barrios-Gonzales, D., Commo, F., et al., Molecular characteristics of ERCC1-negative versus ERCC1-positive tumors in resected NSCLC, Clin. Cancer Res., 2011, vol. 17, no. 17, pp. 5562–5572.
Li, Y., Jiang, Q., Xia, N., et al., Decreased expression of microRNA-375 in nonsmall cell lung cancer and its clinical significance, J. Int. Med. Res., 2012, no. 5, pp. 1662–1669.
Ponomareva, A.A., Rykova, E.Yu., and Cherdyntseva, N.V., et al., Molecular and genetic markers in diagnostics of lung cancer, Mol. Biol. (Moscow), 2011, vol. 45, no. 2, pp. 175–189.
Hsu, H.S., Chen, T.P., Hung, C.H., et al., Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma, Cancer, 2007, vol. 110, no. 9, pp. 2019–2026.
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Original Russian Text © S.V. Rykov, D.S. Khodyrev, I.V. Pronina, T.P. Kazubskaya, V.I. Loginov, E.A. Braga, 2013, published in Genetika, 2013, Vol. 49, No. 7, pp. 896–901.
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Rykov, S.V., Khodyrev, D.S., Pronina, I.V. et al. Novel miRNA genes methylated in lung tumors. Russ J Genet 49, 782–786 (2013). https://doi.org/10.1134/S1022795413070119
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DOI: https://doi.org/10.1134/S1022795413070119