Изменение метилирования группы апоптоз-ассоциированных белок-кодирующих генов и генов длинных некодирующих РНК как фактор в нарушении их экспрессии при раке молочной железы

Alyona Dmitrievna Selezneva; Svetlana Sergeevna Lukina; Anna Dmitrievna Selezneva; Irina Valeryevna Pronina; Dina Mironovna Merkulova; Tatiana Pavlovna Kazubskaya; Alexey Mikhailovich Budyonny; Eleonora Alexandrovna Braga; Vitaly Igorevich Loginov

doi:10.25557/0031-2991.2024.04.4-13

Alyona Dmitrievna Selezneva Research Institute of General Pathology and Pathophysiology, 8 Baltiyskaya st., Moscow, 125315, Russian Federation https://orcid.org/0009-0001-5472-8879
Svetlana Sergeevna Lukina Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow, 125315, Russian Federation https://orcid.org/0000-0001-6246-2444
Anna Dmitrievna Selezneva Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow, 125315, Russian Federation https://orcid.org/0009-0000-0741-3965
Irina Valeryevna Pronina Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow, 125315, Russian Federation; 2State University of Education, Faculty of Natural Sciences, Department of Physiology, Human Ecology and Biomedical Knowledge https://orcid.org/0000-0002-0423-7801
Dina Mironovna Merkulova I.M . Sechenov First Moscow State Medical University of the Ministry of Healthcare of the Trubetskaya ul.,119991 Moscow, Russian Federation
Tatiana Pavlovna Kazubskaya N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, 23 Kashirskoye highway, Moscow, 115478, Russian Federation https://orcid.org/0000-0001-5856-0017
Alexey Mikhailovich Budyonny Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow, 125315, Russian Federation;N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosygina st., Moscow, 119334, Russian Federation https://orcid.org/0000-0002-9398-8075
Eleonora Alexandrovna Braga Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow, 125315, Russian Federation; Research Centre for Medical Genetics, 1 Moskvorechye st., Moscow, 115522, Russian Federation https://orcid.org/0000-0001-5188-4094
Vitaly Igorevich Loginov Institute of General Pathology and Pathophysiology, Baltiyskaya St. 8, Moscow, 125315, Russian Federation; Research Centre for Medical Genetics, 1 Moskvorechye st., Moscow, 115522, Russian Federation https://orcid.org/0000-0003-2668-8096

DOI: https://doi.org/10.25557/0031-2991.2024.04.4-13

Keywords: DNA methylation, apoptosis-associated protein-coding genes, long non-coding RNAs, breast cancer

Abstract

Background and aims. This study focused on the role of changes in DNA methylation and mRNA expression of protein-coding genes of the intrinsic apoptosis system APAF1, BAX, and BIM, and long non-coding RNA (lncRNA) genes ADAMTS9-AS2 and HAND2-AS1 in the emergence and progression of breast cancer (BC), as well as on the analysis of co-methylation and co-expression of representatives from these two gene groups.

Methods. Analysis of methylation level was performed by quantitative methyl-specific real-time PCR on a sample of 47 paired (tumor/adjacent histologically normal breast tissue) BC specimens. The expression levels were evaluated by reverse transcription followed by cDNA amplification using SYBR Green real-time PCR. The significance of differences between the studied groups was assessed with the non-parametric Mann–Whitney test for independent samples. Differences were considered significant at p≤0.05.

Results. The methylation level of all studied genes was significantly increased whereas the expression level of APAF1 and ADAMTS9-AS2 genes was significantly decreased in breast tumor tissue. Significant associations were found between the methylation level of BAX, APAF1, HAND2-AS1, and ADAMTS9-AS2 genes with stage, HAND2-AS1 gene with tumor size, and BIM gene with the presence of lymph node metastases. The study also demonstrated an association between changes in the expression level of BIM and APAF1 genes and BC progression indicators (stage and tumor size). A significant negative correlation was shown between changes in the methylation status of promoter CpG islands of APAF1, BAX, and ADAMTS9-AS2 genes and changes in their expression levels. Co-methylation of ADAMTS9-AS2 – BIM/APAF1/BAX and HAND2-AS1 – BAX genes, and co-expression of ADAMTS9-AS2 – BAX genes were detected.

Conclusion. The obtained results can justify the use of the studied genes as markers for BC diagnosis and prognosis.

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Сhanges in methylation of a group of apoptosis-associated protein-coding genes and long non-coding RNA genes as a factor of dysregulation of their expression in breast cancer

Abstract

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