Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer

High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents (i.e., platinum and poly(ADP-ribose) polymerase inhibitors [PARPis]) due to an underlying defect in homologous recombination (HR). However, r...

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Vydáno v:	Cell reports (Cambridge) Ročník 14; číslo 3; s. 429 - 439
Hlavní autoři:	Choi, Young Eun, Meghani, Khyati, Brault, Marie-Eve, Leclerc, Lucas, He, Yizhou J., Day, Tovah A., Elias, Kevin M., Drapkin, Ronny, Weinstock, David M., Dao, Fanny, Shih, Karin K., Matulonis, Ursula, Levine, Douglas A., Konstantinopoulos, Panagiotis A., Chowdhury, Dipanjan
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 26.01.2016 Elsevier
Témata:	Animals Antigens, Nuclear - genetics Antigens, Nuclear - metabolism Antineoplastic Agents - pharmacology Base Sequence BRCA1 Protein - genetics BRCA1 Protein - metabolism Cell Line, Tumor Disease-Free Survival DNA End-Joining Repair - drug effects DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Female Homologous Recombination - drug effects Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Ku Autoantigen Mice MicroRNAs - antagonists & inhibitors MicroRNAs - genetics MicroRNAs - metabolism Oligonucleotides, Antisense - metabolism Organoplatinum Compounds - pharmacology Ovarian Neoplasms - genetics Ovarian Neoplasms - mortality Ovarian Neoplasms - pathology Poly(ADP-ribose) Polymerase Inhibitors - pharmacology RNA Interference Sequence Alignment Tumor Suppressor p53-Binding Protein 1
ISSN:	2211-1247, 2211-1247
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Shrnutí:	High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents (i.e., platinum and poly(ADP-ribose) polymerase inhibitors [PARPis]) due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum-resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622, induces resistance to PARPis and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue. [Display omitted] •miR-622 induces resistance to PARP inhibitors and cisplatin in BRCA1-deficient cells•miR-622 levels in BRCA1-mutant ovarian tumors correlates with survival of patients•The Ku complex is directly downregulated by miR-622 to suppress the NHEJ pathway•MiR-622 helps to balance HR and NHEJ pathways for DSB repair during the cell cycle Choi et al. show that expression of miR-622 induces resistance to PARP inhibitors and cisplatin in BRCA1-mutant ovarian tumors and correlates with survival of patients. miR-622 suppresses NHEJ by downregulating expression of the Ku complex and facilitates homologous recombination mediated repair of DNA double-strand breaks (DSBs) in the S phase of cycling cells.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2015.12.046