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Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium

BACKGROUND: Loss of the genomic stability jeopardize genome stability and promote malignancies. A fraction of ovarian cancer (OvCa) arises from pathological mutations of DNA repair genes that result in highly mutagenic genomes. However, it remains elusive why the ovarian epithelial cells are particu...

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Autores principales: Song, Liang, Tang, Zizhi, Peng, Changsheng, Yang, Yueming, Guo, Chang, Wang, Danqing, Guo, Liandi, Chen, Jie, Liu, Cong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579787/
https://www.ncbi.nlm.nih.gov/pubmed/33087072
http://dx.doi.org/10.1186/s12885-020-07524-7
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author Song, Liang
Tang, Zizhi
Peng, Changsheng
Yang, Yueming
Guo, Chang
Wang, Danqing
Guo, Liandi
Chen, Jie
Liu, Cong
author_facet Song, Liang
Tang, Zizhi
Peng, Changsheng
Yang, Yueming
Guo, Chang
Wang, Danqing
Guo, Liandi
Chen, Jie
Liu, Cong
author_sort Song, Liang
collection PubMed
description BACKGROUND: Loss of the genomic stability jeopardize genome stability and promote malignancies. A fraction of ovarian cancer (OvCa) arises from pathological mutations of DNA repair genes that result in highly mutagenic genomes. However, it remains elusive why the ovarian epithelial cells are particularly susceptible to the malfunction of genome surveillance system. METHODS: To explore the genotoxic responses in the unique context of microenvironment for ovarian epithelium that is periodically exposed to high-level steroid hormones, we examined estrogen-induced DNA damage by immunofluorescence in OvCa cell lines, animal and human samples. RESULTS: We found that OvCa cells are burdened with high levels of endogenous DNA damage that is not correlated with genomic replication. The elevation of damage burden is attributable to the excessive concentration of bioactive estrogen instead of its chemomimetic derivative (tamoxifen). Induction of DNA lesions by estrogen is dependent on the expression of hormone receptors, and occurs in G1 and non-G1 phases of cell cycle. Moreover, depletion of homologous recombination (HR) genes (BRCA1 and BRCA2) exacerbated the genotoxicity of estrogen, highlighting the role of HR to counteract hormone-induced genome instability. Finally, the estrogen-induced DNA damage was reproduced in the epithelial compartments of both ovarian and fallopian tubes. CONCLUSIONS: Taken together, our study disclose that estrogen-induced genotoxicity and HR deficiency perturb the genome stability of ovarian and fallopian epithelial cells, representing microenvironmental and genetic risk factors, respectively. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s12885-020-07524-7.
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spelling pubmed-75797872020-10-22 Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium Song, Liang Tang, Zizhi Peng, Changsheng Yang, Yueming Guo, Chang Wang, Danqing Guo, Liandi Chen, Jie Liu, Cong BMC Cancer Research Article BACKGROUND: Loss of the genomic stability jeopardize genome stability and promote malignancies. A fraction of ovarian cancer (OvCa) arises from pathological mutations of DNA repair genes that result in highly mutagenic genomes. However, it remains elusive why the ovarian epithelial cells are particularly susceptible to the malfunction of genome surveillance system. METHODS: To explore the genotoxic responses in the unique context of microenvironment for ovarian epithelium that is periodically exposed to high-level steroid hormones, we examined estrogen-induced DNA damage by immunofluorescence in OvCa cell lines, animal and human samples. RESULTS: We found that OvCa cells are burdened with high levels of endogenous DNA damage that is not correlated with genomic replication. The elevation of damage burden is attributable to the excessive concentration of bioactive estrogen instead of its chemomimetic derivative (tamoxifen). Induction of DNA lesions by estrogen is dependent on the expression of hormone receptors, and occurs in G1 and non-G1 phases of cell cycle. Moreover, depletion of homologous recombination (HR) genes (BRCA1 and BRCA2) exacerbated the genotoxicity of estrogen, highlighting the role of HR to counteract hormone-induced genome instability. Finally, the estrogen-induced DNA damage was reproduced in the epithelial compartments of both ovarian and fallopian tubes. CONCLUSIONS: Taken together, our study disclose that estrogen-induced genotoxicity and HR deficiency perturb the genome stability of ovarian and fallopian epithelial cells, representing microenvironmental and genetic risk factors, respectively. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s12885-020-07524-7. BioMed Central 2020-10-21 /pmc/articles/PMC7579787/ /pubmed/33087072 http://dx.doi.org/10.1186/s12885-020-07524-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Song, Liang
Tang, Zizhi
Peng, Changsheng
Yang, Yueming
Guo, Chang
Wang, Danqing
Guo, Liandi
Chen, Jie
Liu, Cong
Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
title Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
title_full Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
title_fullStr Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
title_full_unstemmed Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
title_short Cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
title_sort cell type-specific genotoxicity in estrogen-exposed ovarian and fallopian epithelium
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579787/
https://www.ncbi.nlm.nih.gov/pubmed/33087072
http://dx.doi.org/10.1186/s12885-020-07524-7
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