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Upregulation of RHOA and NKIRAS1 Genes in Lung Tumors Is Associated with Loss of Their Methylation as well as with Methylation of Regulatory miRNA Genes

E. A. Braga1,2*, V. I. Loginov1,2, I. V. Pronina1,2, D. S. Khodyrev3, S. V. Rykov4, A. M. Burdennyy1, M. V. Friedman5, T. P. Kazubskaya6, A. A. Kubatiev1, and N. E. Kushlinskii6

1Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; fax: +7 (495) 601-2366; E-mail: eleonora10_45@mail.ru

2Research Center of Medical Genetics, Russian Academy of Medical Sciences, 115478 Moscow, Russia; fax: +7 (499) 324-0702; E-mail: karpukhin@med-gen.ru

3Federal Research Clinical Center of Specialized Types of Medical Care and Medical Technologies, Federal Medical and Biological Agency of Russia, 115682 Moscow, Russia; fax: +7 (495) 395-6430; E-mail: DmKh8@mail.ru

4State Research Institute of Genetics and Selection of Industrial Microorganisms, 117545 Moscow, Russia; fax: +7 (495) 315-0501; E-mail: genetika@genetika.ru

5Vavilov Institute of General Genetics, Russian Academy of Sciences, 117971 Moscow, Russia; fax: +7 (499) 135-6213; E-mail: iogen@vigg.ru

6Blokhin Russian Cancer Research Center, 115478 Moscow, Russia; fax: +7 (499) 324-6352; E-mail: biochimia@mtu-net.ru

* To whom correspondence should be addressed.

Received November 30, 2014; Revision received January 19, 2015
Methylation of CpG-islands in promoter regions as well as interaction of miRNAs with messenger RNAs of target genes are related to multilayer mechanisms regulating gene expression. The goal of this study was to assess a possibility for miRNA gene methylation to influence indirectly activation of their target genes in lung tumors. By using a unified collection of samples of non-small cell lung cancer, it was demonstrated that elevated levels of mRNA for RHOA and NKIRAS1 genes were significantly (Spearman rank correlation, P < 10–11) associated both with loss of methylation in their CpG-islands and methylation in a number of miRNA genes, which, according to the miRWalk database, were predicted to possess regulatory functions. Novel potential regulatory miRNAs for RHOA (miR-9-1/-3, -34b/c, -129-2, -125b-1, -375, -1258) and NKIRAS1 (miR-34b/c, -129-2, -125b-1, -193a, -124a-1/-2/-3, -212, -132) genes in lung cancer were identified.
KEY WORDS: CpG-islands, methylation, miRNA, target genes, RHOA, NKIRAS1, mRNA, lung cancer

DOI: 10.1134/S0006297915040124