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| Content Provider | frontiers |
|---|---|
| Author | Bagnoli, Marina Nicoletti, Roberta Valitutti, Monica Rizzo, Andrea Napoli, Alessandra Montalvão De Azevedo, Rafaela Tomassetti, Antonella Mezzanzanica, Delia |
| Abstract | 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. |
| ISSN | 2234943X |
| DOI | 10.3389/fonc.2022.923508 |
| Volume Number | 12 |
| Journal | Frontiers in Oncology |
| Language | English |
| Publisher Date | 2022-07-18 |
| Access Restriction | Open |
| Subject Keyword | MiR-506-3p ChrXq27.3 miRNA cluster DNA damage and repair Cell cycle checkpoint inhibitors RAD17 Ovarian cancer ovarian cancer cell cycle checkpoint inhibitors |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology |
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