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Constitutive Expression of NRAS with Q61R Driver Mutation Activates Processes of Epithelial–Mesenchymal Transition and Leads to Substantial Transcriptome Change of Nthy-ori 3-1 Thyroid Epithelial Cells


D. E. Demin1,2, M. A. Afanasyeva1, A. N. Uvarova1, M. M. Prokofjeva1, A. M. Gorbachova1, A. S. Ustiugova1, A. V. Klepikova3,4, L. V. Putlyaeva1, K. A. Tatosyan1, P. V. Belousov1, and A. M. Schwartz1,2,a*

1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

2Moscow Institute of Physics and Technology, 141701 Moscow, Russia

3Institute for Information Transmission Problems, Russian Academy of Sciences, 127051 Moscow, Russia

4Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

* To whom correspondence should be addressed.

Received October 10, 2018; Revised December 4, 2018; Accepted December 4, 2018
The Q61R mutation of the NRAS gene is one of the most frequent driver mutations of thyroid cancer. Tumors with this mutation are characterized by invasion into blood vessels and formation of distant metastases. To study the role of this mutation in the growth of thyroid cancer, we developed a model system on the basis of thyroid epithelial cell line Nthy-ori 3-1 transduced by a lentiviral vector containing the NRAS gene with the Q61R mutation. It was found that the expression of NRAS(Q61R) in thyroid epithelial cells has a profound influence on groups of genes involved in the formation of intercellular contacts, as well as in processes of epithelial–mesenchymal transition and cell invasion. The alteration in the expression of these genes affects the phenotype of the model cells, which acquire traits of mesenchymal cells and demonstrate increased ability for survival and growth without attachment to the substrate. The key regulators of these processes are transcription factors belonging to families SNAIL, ZEB, and TWIST, and in different types of tumors the contribution of each individual factor can vary greatly. In our model system, phenotype change correlates with an increase in the expression of SNAIL2 and TWIST2 factors, which indicates their possible role in regulating invasive growth of thyroid cancer with the mutation of NRAS(Q61R).
KEY WORDS: thyroid cancer, invasive growth, epithelial–mesenchymal transition, NRAS(Q61R), SNAIL, TWIST

DOI: 10.1134/S0006297919040096