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Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucl...

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Autores principales: Simonova, Olga A., Kuznetsova, Ekaterina B., Tanas, Alexander S., Rudenko, Viktoria V., Poddubskaya, Elena V., Kekeeva, Tatiana V., Trotsenko, Ivan D., Larin, Sergey S., Kutsev, Sergei I., Zaletaev, Dmitry V., Nemtsova, Marina V., Strelnikov, Vladimir V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277193/
https://www.ncbi.nlm.nih.gov/pubmed/32397602
http://dx.doi.org/10.3390/biomedicines8050116
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author Simonova, Olga A.
Kuznetsova, Ekaterina B.
Tanas, Alexander S.
Rudenko, Viktoria V.
Poddubskaya, Elena V.
Kekeeva, Tatiana V.
Trotsenko, Ivan D.
Larin, Sergey S.
Kutsev, Sergei I.
Zaletaev, Dmitry V.
Nemtsova, Marina V.
Strelnikov, Vladimir V.
author_facet Simonova, Olga A.
Kuznetsova, Ekaterina B.
Tanas, Alexander S.
Rudenko, Viktoria V.
Poddubskaya, Elena V.
Kekeeva, Tatiana V.
Trotsenko, Ivan D.
Larin, Sergey S.
Kutsev, Sergei I.
Zaletaev, Dmitry V.
Nemtsova, Marina V.
Strelnikov, Vladimir V.
author_sort Simonova, Olga A.
collection PubMed
description Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucleotides in promoter regions of the MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28, TIMP1, TIMP2, TIMP3, and TIMP4 genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in MMP2, MMP23B, MMP24, MMP25, and MMP28 promoter regions. The non-methylated status of the examined CpGs in promoter regions of MMP2, MMP23B, MMP24, MMP25, and MMP28 in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of MMP24 and MMP25 was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis.
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spelling pubmed-72771932020-06-15 Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression Simonova, Olga A. Kuznetsova, Ekaterina B. Tanas, Alexander S. Rudenko, Viktoria V. Poddubskaya, Elena V. Kekeeva, Tatiana V. Trotsenko, Ivan D. Larin, Sergey S. Kutsev, Sergei I. Zaletaev, Dmitry V. Nemtsova, Marina V. Strelnikov, Vladimir V. Biomedicines Article Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) substantially contribute to the regulation of intercellular interactions and thereby play a role in maintaining the tissue structure and function. We examined methylation of a subset of 5’-cytosine-phosphate-guanine-3’ (CpG) dinucleotides in promoter regions of the MMP2, MMP11, MMP14, MMP15, MMP16, MMP17, MMP21, MMP23B, MMP24, MMP25, MMP28, TIMP1, TIMP2, TIMP3, and TIMP4 genes by methylation-sensitive restriction enzyme digestion PCR. In our collection of 183 breast cancer samples, abnormal hypermethylation was observed for CpGs in MMP2, MMP23B, MMP24, MMP25, and MMP28 promoter regions. The non-methylated status of the examined CpGs in promoter regions of MMP2, MMP23B, MMP24, MMP25, and MMP28 in tumors was associated with low HER2 expression, while the group of samples with abnormal hypermethylation of at least two of these MMP genes was significantly enriched with HER2-positive tumors. Abnormal methylation of MMP24 and MMP25 was significantly associated with a CpG island hypermethylated breast cancer subtype discovered by genome-wide DNA bisulfite sequencing. Our results indicate that abnormal hypermethylation of at least several MMP genes promoters is a secondary event not directly functional in breast cancer (BC) pathogenesis. We suggest that it is elevated and/or ectopic expression, rather than methylation-driven silencing, that might link MMPs to tumorigenesis. MDPI 2020-05-10 /pmc/articles/PMC7277193/ /pubmed/32397602 http://dx.doi.org/10.3390/biomedicines8050116 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Simonova, Olga A.
Kuznetsova, Ekaterina B.
Tanas, Alexander S.
Rudenko, Viktoria V.
Poddubskaya, Elena V.
Kekeeva, Tatiana V.
Trotsenko, Ivan D.
Larin, Sergey S.
Kutsev, Sergei I.
Zaletaev, Dmitry V.
Nemtsova, Marina V.
Strelnikov, Vladimir V.
Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
title Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
title_full Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
title_fullStr Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
title_full_unstemmed Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
title_short Abnormal Hypermethylation of CpG Dinucleotides in Promoter Regions of Matrix Metalloproteinases Genes in Breast Cancer and its Relation to Epigenomic Subtypes and HER2 Overexpression
title_sort abnormal hypermethylation of cpg dinucleotides in promoter regions of matrix metalloproteinases genes in breast cancer and its relation to epigenomic subtypes and her2 overexpression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277193/
https://www.ncbi.nlm.nih.gov/pubmed/32397602
http://dx.doi.org/10.3390/biomedicines8050116
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