LncRNA Genes of the SNHGs Family: Cometylation and Common Functions in Ovarian Cancer

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Abstract

Long non-coding RNA (lncRNA) genes of the small nucleolar RNA host gene family (SNHGs) may participate in oncogenesis both through regulatory functions inherent to lncRNA and through their influence on the formation of small nucleolar RNAs and ribosome biogenesis. The aim of this work is to evaluate changes in the methylation level and the degree of comethylation of a group of lncRNA genes of the SNHGs family (SNHG1, GAS5/SNHG2, SNHG6, SNHG12, SNHG17) in clinical samples of ovarian cancer (OC) for different stages of cancer as a criterion for the similarity of their role in oncogenesis. On a representative set of 122 OC samples, MS-qPCR showed a statistically significant (p < {0.01-0.0001}) increase in the methylation level of 5 studied lncRNA genes. A statistically significant relationship was shown between the increased methylation level of GAS5, SNHG6, SNHG12 and OC progression: with the clinical stage, tumor size and metastasis, which indicates the possible functional significance of hypermethylation of these genes. For 4 of the 5 genes: SNHG1, GAS5, SNHG6, SNHG12, a statistically significant pairwise positive correlation of methylation levels was revealed for the first time (rs > 0.35; p ≤ 0.001). Our data on co-methylation of these 4 genes are in agreement with the GEPIA 2.0 data (for 426 OC samples), revealing their co-expression (rs > 0.5; p < 0.001); the correlation of GAS5 and SNHG6 expression levels was confirmed by quantitative RT-PCR (rs = 0.46; p = 0.007). For lncRNA SNHG1, GAS5, SNHG6 and SNHG12, common miRNAs were predicted bioinformatically, potentially capable of interacting with one or more of them via the mechanism of competing endogenous RNAs. The mRNAs, the expression of which they are thus capable of influencing, were also predicted. The possible involvement of genes corresponding to these mRNAs in a number of processes significant for oncogenesis, including RNA processing and splicing and epithelial-mesenchymal transition, was studied. Thus, 4 lncRNAs of the SNHGs family were identified, which have similarities both in their regulation and in their putative biological functions in the pathogenesis of OC.

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About the authors

E. A. Braga

Research Institute of General Pathology and Pathophysiology

Author for correspondence.
Email: eleonora10_45@mail.ru
Russian Federation, 125315, Moscow

E. A. Filippova

Research Institute of General Pathology and Pathophysiology

Email: eleonora10_45@mail.ru
Russian Federation, 125315, Moscow

L. A. Uroshlev

Vavilov Institute of General Genetics of the Russian Academy of Sciences

Email: eleonora10_45@mail.ru
Russian Federation, 119991 Moscow

S. S. Lukina

Research Institute of General Pathology and Pathophysiology

Email: eleonora10_45@mail.ru
Russian Federation, 125315, Moscow

I. V. Pronina

Research Institute of General Pathology and Pathophysiology

Email: eleonora10_45@mail.ru
Russian Federation, 125315, Moscow

T. P. Kazubskaya

Blokhin National Medical Research Center of Oncology

Email: eleonora10_45@mail.ru
Russian Federation, 115522, Moscow

D. N. Kushlinsky

Blokhin National Medical Research Center of Oncology

Email: eleonora10_45@mail.ru
Russian Federation, 115522, Moscow

V. I. Loginov

Research Institute of General Pathology and Pathophysiology

Email: eleonora10_45@mail.ru
Russian Federation, 125315, Moscow

M. V. Fridman

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: eleonora10_45@mail.ru
Russian Federation, 119991, Moscow

A. M. Burdenny

Research Institute of General Pathology and Pathophysiology

Email: burdennyy@gmail.com
Russian Federation, 125315, Moscow

N. E. Kushlinsky

Blokhin National Medical Research Center of Oncology

Email: eleonora10_45@mail.ru
Russian Federation, 115522, Moscow

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2. Fig. 1. Changes in methylation levels of 5 dnRNA genes of the SNHG gene family in ovarian tumours; GAS5 and SNHG6 genes were examined in 122 tumour samples and 105 normal samples; SNHG1, SNHG12, SNHG17 genes were examined in 93 tumour samples and 75 normal samples; ** p < 0.01, # p < 0.0001; N, paired normal ovarian tissue samples; T, ovarian cancer tumour samples

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3. Fig. 2. Correlation of methylation levels of GAS5, SNHG6 and SNHG12 genes with RN progression; a - with clinical stage (I-II - 45 RN samples, III-IV - 77 RN samples); b - with cancer size and spread (T1 + T2 - 46 RN samples, T3 - 76 RN samples); c - with metastasis to lymph nodes (N0 - 101 RN samples, N1 - 21 RN samples); d - with dissemination to peritoneum and omentum (none - 45, 77); e - taking into account all types of metastasis (43 - none, 79 - yes); * p < 0.05; ** p < 0.01; *** p < 0.001; # p < 0.0001

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4. Fig. 3. Correlation matrix showing the degree of correlation between methylation levels of 5 dnRNA genes (GAS5, SNHG1, SNHG6, SNHG12, SNHG17) in RND (pairwise correlations for 5 genes in 93 RND samples, except for the GAS5 - SNHG6 pair, for which correlation was determined in 122 total samples). Positive correlations are shown in red, negative correlations in blue; colour intensity is equivalent to the Spearman correlation coefficient

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5. Fig. 4. Changes in expression levels of the 5 dnRNAs GAS5, SNHG1, SNHG6, SNHG12, SNHG17, in serous ovarian cystadenocarcinoma, according to GEPIA 2.0 (red in tumour, dark grey in normal); 426 tumour samples, 88 normal tissue samples; red asterisk corresponds to p < 0.01; TPM, transcripts per million mapped reads)

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6. Fig. 5. Positive correlations between changes in expression levels in 6 pairs of 4 dnRNAs of the SNHG family, according to GEPIA 2.0 data (sample: 426 ovarian serous cystadenocarcinoma samples, 88 normal samples). Spearman correlation coefficient (rs) and significance (p-value) are given

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7. Fig. 6. Detection of concerted regulation among a group of dnRNA genes of the SNHG family. a - Changes in expression levels of 4 dnRNAs GAS5, SNHG6, SNHG12, SNHG17 in tumour samples relative to normal tissue; GAS5 was examined in a sample of 68 paired RN samples; SNHG6 - in 57 paired RN samples; SNHG12, SNHG17 - in 29 paired RN samples. b - Positive correlation between GAS5 and SNHG6 dnRNA expression levels in a sample of 33 total RN samples. c - Negative correlation between GAS5 dnRNA expression levels and methylation in a sample of 53 total RN samples; d - Negative correlation between SNHG6 dnRNA expression levels and methylation in a sample of 30 total RN samples. The Spearman correlation coefficient (rs) was calculated

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8. Fig. 7. Detection of co-regulated miRNAs. a - Expression levels of miR-124-3p, miR-124-5p, miR-137-3p in ovarian tumour samples relative to paired normal; miR-124-3p was examined in 38 paired RN samples, miR-124-5p in 44 RN samples, miR-137-3p in 41 RN samples. b - Negative correlation of GAS5 and miR-124-5p dnRNA expression levels in a sample of 28 total paired RN samples

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9. Fig. 8. Venn diagrams of mRNAs co-expressed with GAS5, SNHG1, SNHG6 and SNHG12 and scatter plots showing processes common to the 4 pairwise dnRNA combinations in RND; processes predicted by gprofiler2 and data from GO, REAC, KEGG, HP, HPA, CORUM, TF, WP (p < 0.05)

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