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Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos
In vitro fertilization (IVF) increases the risk of tumorigenesis in offspring. The increased oxidative damage during IVF may be involved in tumor formation. However, the molecular mechanisms underlying this phenomenon remain largely unclear. Using a well-established model of oxidatively damaged IVF...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640061/ https://www.ncbi.nlm.nih.gov/pubmed/34848840 http://dx.doi.org/10.1038/s12276-021-00700-0 |
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author | Huang, Yue Li, Zhiling Lin, En He, Pei Ru, Gaizhen |
author_facet | Huang, Yue Li, Zhiling Lin, En He, Pei Ru, Gaizhen |
author_sort | Huang, Yue |
collection | PubMed |
description | In vitro fertilization (IVF) increases the risk of tumorigenesis in offspring. The increased oxidative damage during IVF may be involved in tumor formation. However, the molecular mechanisms underlying this phenomenon remain largely unclear. Using a well-established model of oxidatively damaged IVF mouse embryos, we applied the iTRAQ method to identify proteins differentially expressed between control and oxidatively damaged zygotes and explored the possible tumorigenic mechanisms, especially with regard to the effects of oxidative damage on ribosome biogenesis closely related to tumorigenesis. The iTRAQ results revealed that ribosomal proteins were upregulated by oxidative stress through the Nucleolin/β-Catenin/n-Myc pathway, which stimulated ribosomes to synthesize an abundance of repair proteins to correct the damaged DNA/chromosomes in IVF-derived embryos. However, the increased percentages of γH2AX-positive cells and apoptotic cells in the blastocyst suggested that DNA repair was insufficient, resulting in aberrant ribosome biogenesis. Overexpression of ribosomal proteins, particularly Rpl15, which gradually increased from the 1-cell to 8-cell stages, indicated persistent hyperactivation of ribosome biogenesis, which promoted tumorigenesis in offspring derived from oxidatively damaged IVF embryos by selectively enhancing the translation of β-Catenin and TGF-β1. The antioxidant epigallocatechin-3-gallate (EGCG) was added to the in vitro culture medium to protect embryos from oxidative damage, and the expression of ribosome-/tumor-related proteins returned to normal after EGCG treatment. This study suggests that regulation of ribosome biogenesis by EGCG may be a means of preventing tumor formation in human IVF-derived offspring, providing a scientific basis for optimizing in vitro culture conditions and improving human-assisted reproductive technology. |
format | Online Article Text |
id | pubmed-8640061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86400612021-12-10 Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos Huang, Yue Li, Zhiling Lin, En He, Pei Ru, Gaizhen Exp Mol Med Article In vitro fertilization (IVF) increases the risk of tumorigenesis in offspring. The increased oxidative damage during IVF may be involved in tumor formation. However, the molecular mechanisms underlying this phenomenon remain largely unclear. Using a well-established model of oxidatively damaged IVF mouse embryos, we applied the iTRAQ method to identify proteins differentially expressed between control and oxidatively damaged zygotes and explored the possible tumorigenic mechanisms, especially with regard to the effects of oxidative damage on ribosome biogenesis closely related to tumorigenesis. The iTRAQ results revealed that ribosomal proteins were upregulated by oxidative stress through the Nucleolin/β-Catenin/n-Myc pathway, which stimulated ribosomes to synthesize an abundance of repair proteins to correct the damaged DNA/chromosomes in IVF-derived embryos. However, the increased percentages of γH2AX-positive cells and apoptotic cells in the blastocyst suggested that DNA repair was insufficient, resulting in aberrant ribosome biogenesis. Overexpression of ribosomal proteins, particularly Rpl15, which gradually increased from the 1-cell to 8-cell stages, indicated persistent hyperactivation of ribosome biogenesis, which promoted tumorigenesis in offspring derived from oxidatively damaged IVF embryos by selectively enhancing the translation of β-Catenin and TGF-β1. The antioxidant epigallocatechin-3-gallate (EGCG) was added to the in vitro culture medium to protect embryos from oxidative damage, and the expression of ribosome-/tumor-related proteins returned to normal after EGCG treatment. This study suggests that regulation of ribosome biogenesis by EGCG may be a means of preventing tumor formation in human IVF-derived offspring, providing a scientific basis for optimizing in vitro culture conditions and improving human-assisted reproductive technology. Nature Publishing Group UK 2021-11-30 /pmc/articles/PMC8640061/ /pubmed/34848840 http://dx.doi.org/10.1038/s12276-021-00700-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Huang, Yue Li, Zhiling Lin, En He, Pei Ru, Gaizhen Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos |
title | Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos |
title_full | Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos |
title_fullStr | Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos |
title_full_unstemmed | Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos |
title_short | Oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the Wnt and TGF-β1 pathways in IVF embryos |
title_sort | oxidative damage-induced hyperactive ribosome biogenesis participates in tumorigenesis of offspring by cross-interacting with the wnt and tgf-β1 pathways in ivf embryos |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640061/ https://www.ncbi.nlm.nih.gov/pubmed/34848840 http://dx.doi.org/10.1038/s12276-021-00700-0 |
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