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Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer
Epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer and development of chemo-resistance is a major factor in disease relapse. Homologous recombination (HR) is a critical pathway for DNA double strand break repair and its deficiency is associated to a better response to DNA d...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340372/ https://www.ncbi.nlm.nih.gov/pubmed/35924161 http://dx.doi.org/10.3389/fonc.2022.923508 |
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author | Bagnoli, Marina Nicoletti, Roberta Valitutti, Monica Rizzo, Andrea Napoli, Alessandra Montalvão De Azevedo, Rafaela Tomassetti, Antonella Mezzanzanica, Delia |
author_facet | Bagnoli, Marina Nicoletti, Roberta Valitutti, Monica Rizzo, Andrea Napoli, Alessandra Montalvão De Azevedo, Rafaela Tomassetti, Antonella Mezzanzanica, Delia |
author_sort | Bagnoli, Marina |
collection | PubMed |
description | Epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer and development of chemo-resistance is a major factor in disease relapse. Homologous recombination (HR) is a critical pathway for DNA double strand break repair and its deficiency is associated to a better response to DNA damage-inducing agents. Strategies to inhibit HR-mediated DNA repair is a clinical need to improve patients’ outcome. MicroRNA (miRNAs) affect most of cellular processes including response to cancer treatment. We previously showed that miR-506-3p targets RAD51, an essential HR component. In this study we demonstrated that: i) another HR component, RAD17, is also a direct target of miR-506-3p and that it is involved in mediating miR-506-3p phenotypic effects; ii) the impairment of miR-506-3p binding to RAD17 3’ UTR reverted the miR-506-3p induced platinum sensitization; iii) miR-506-3p/RAD17 axis reduces the ability of EOC cell to sense DNA damage, abrogates the G2/M cell cycle checkpoint thus delaying the G2/M cell cycle arrest likely allowing the entry into mitosis of heavily DNA-damaged cells with a consequent mitotic catastrophe; iv) RAD17 expression, regulated by miR-506-3p, is synthetically lethal with inhibitors of cell cycle checkpoint kinases Chk1 and Wee1 in platinum resistant cell line. Overall miR-506-3p expression may recapitulate a BRCAness phenotype sensitizing EOC cells to chemotherapy and helping in selecting patients susceptible to DNA damaging drugs in combination with new small molecules targeting DNA-damage repair pathway. |
format | Online Article Text |
id | pubmed-9340372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93403722022-08-02 Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer Bagnoli, Marina Nicoletti, Roberta Valitutti, Monica Rizzo, Andrea Napoli, Alessandra Montalvão De Azevedo, Rafaela Tomassetti, Antonella Mezzanzanica, Delia Front Oncol Oncology Epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer and development of chemo-resistance is a major factor in disease relapse. Homologous recombination (HR) is a critical pathway for DNA double strand break repair and its deficiency is associated to a better response to DNA damage-inducing agents. Strategies to inhibit HR-mediated DNA repair is a clinical need to improve patients’ outcome. MicroRNA (miRNAs) affect most of cellular processes including response to cancer treatment. We previously showed that miR-506-3p targets RAD51, an essential HR component. In this study we demonstrated that: i) another HR component, RAD17, is also a direct target of miR-506-3p and that it is involved in mediating miR-506-3p phenotypic effects; ii) the impairment of miR-506-3p binding to RAD17 3’ UTR reverted the miR-506-3p induced platinum sensitization; iii) miR-506-3p/RAD17 axis reduces the ability of EOC cell to sense DNA damage, abrogates the G2/M cell cycle checkpoint thus delaying the G2/M cell cycle arrest likely allowing the entry into mitosis of heavily DNA-damaged cells with a consequent mitotic catastrophe; iv) RAD17 expression, regulated by miR-506-3p, is synthetically lethal with inhibitors of cell cycle checkpoint kinases Chk1 and Wee1 in platinum resistant cell line. Overall miR-506-3p expression may recapitulate a BRCAness phenotype sensitizing EOC cells to chemotherapy and helping in selecting patients susceptible to DNA damaging drugs in combination with new small molecules targeting DNA-damage repair pathway. Frontiers Media S.A. 2022-07-18 /pmc/articles/PMC9340372/ /pubmed/35924161 http://dx.doi.org/10.3389/fonc.2022.923508 Text en Copyright © 2022 Bagnoli, Nicoletti, Valitutti, Rizzo, Napoli, Montalvão De Azevedo, Tomassetti and Mezzanzanica https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Bagnoli, Marina Nicoletti, Roberta Valitutti, Monica Rizzo, Andrea Napoli, Alessandra Montalvão De Azevedo, Rafaela Tomassetti, Antonella Mezzanzanica, Delia Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer |
title | Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer |
title_full | Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer |
title_fullStr | Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer |
title_full_unstemmed | Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer |
title_short | Impairment of RAD17 Functions by miR-506-3p as a Novel Synthetic Lethal Approach Targeting DNA Repair Pathways in Ovarian Cancer |
title_sort | impairment of rad17 functions by mir-506-3p as a novel synthetic lethal approach targeting dna repair pathways in ovarian cancer |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340372/ https://www.ncbi.nlm.nih.gov/pubmed/35924161 http://dx.doi.org/10.3389/fonc.2022.923508 |
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