LncRNA Genes of the SNHG Family: Co-methylation and Common Functions in Ovarian Cancer

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Eleonora A. Braga^1,a*, Elena A. Filippova¹, Leonid A. Uroshlev², Svetlana S. Lukina¹, Irina V. Pronina¹, Tatyana P. Kazubskaya³, Dmitry N. Kushlinskiy³, Vitaliy I. Loginov¹, Marina V. Fridman², Alexey M. Burdennyy^1,b*, Nikolay E. Kushlinskii³

¹Research Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia

²Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia

³Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, 115522 Moscow, Russia

^* To whom correspondence should be addressed.

Received: July 4, 2024; Revised: September 1, 2024; Accepted: September 3, 2024

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Genes of the small nucleolar RNA host gene (SNHG) family may participate in oncogenesis through the regulatory functions of encoded long non-coding RNAs (lncRNAs) and by influencing formation of small nucleolar RNAs and ribosome biogenesis. The aim of this work was to evaluate changes in the methylation levels and extent of co-methylation of the SNHG family lncRNA genes (SNHG1, GAS5/SNHG2, SNHG6, SNHG12, SNHG17) in clinical samples of ovarian cancer (OC) as an indication for the similarity of their roles in oncogenesis. Analysis of a representative set of 122 OC samples by quantitative methylation-specific PCR showed a statistically significant (p < 0.01-0.0001) increase in the methylation level of all five studied lncRNA genes. There was also a correlation between the increased methylation levels of GAS5, SNHG6, and SNHG12 and OC progression (clinical stage, tumor size, and metastasis), indicating possible functional significance of hypermethylation of these genes. For four genes (SNHG1, GAS5, SNHG6, and SNHG12), a statistically significant pairwise positive correlation of methylation levels (co-methylation) was observed (r_s > 0.35; p ≤ 0.001), which was in agreement with the GEPIA 2.0 data (426 OC samples) showing co-expression of these genes (r_s > 0.5; p < 0.001). The correlation between the expression levels of GAS5 and SNHG6 was confirmed by RT-qPCR (r_s = 0.46; p = 0.007). Bioinformatics analysis predicted miRNAs common for the SNHG1, GAS5, SNHG6, and SNHG12 lncRNA and potentially capable of interacting with one or more of these lncRNAs via competing endogenous RNA mechanism, as well as mRNAs, whose expression might be affected by the studied lncRNAs. We also investigated a possible involvement of genes for these mRNAs in oncogenesis-related processes, such as RNA processing and splicing and epithelial–mesenchymal transition. As a result of this work, four SNHG family lncRNAs with coregulation and joint putative biological functions in the pathogenesis of OC were identified.

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KEY WORDS: ovarian cancer, long noncoding RNAs, small nucleolar RNA host gene family, snoRNA, miRNA, mRNA, RNA processing, RNA splicing, epithelial–mesenchymal transition

DOI: 10.1134/S0006297924110178

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