The NRF2 transcriptional target NQO1 has low mRNA levels in TP53-mutated endometrial carcinomas
| العنوان: | The NRF2 transcriptional target NQO1 has low mRNA levels in TP53-mutated endometrial carcinomas |
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| المؤلفون: | François Goldwasser, Guillaume Beinse, Frédéric Batteux, Brigitte Izac, Sandrine Chouzenoux, Franck Letourneur, Bastien Rance, Nathaniel Edward Bennett Saidu, Bruno Borghese, Jérôme Alexandre, Eric Pasmant, Karen Leroy, Carole Nicco, Pierre-Alexandre Just |
| المصدر: | PLoS ONE PLoS ONE, Vol 14, Iss 3, p e0214416 (2019) |
| بيانات النشر: | Public Library of Science, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Transcription, Genetic, Gene Expression, Mismatch Repair, medicine.disease_cause, Biochemistry, 0302 clinical medicine, Gene expression, Medicine and Health Sciences, NAD(P)H Dehydrogenase (Quinone), Regulation of gene expression, Staining, Aged, 80 and over, Mutation, Multidisciplinary, Kelch-Like ECH-Associated Protein 1, Cell Staining, Middle Aged, Prognosis, Nucleic acids, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Immunohistochemistry, Medicine, Female, Anatomy, Endometrial Carcinoma, Research Article, Adult, Histology, NF-E2-Related Factor 2, Science, DNA repair, Biology, Research and Analysis Methods, Carcinomas, 03 medical and health sciences, Carcinoma, medicine, Genetics, Humans, RNA, Messenger, Gene, Aged, Cancers and Neoplasms, Biology and Life Sciences, DNA, medicine.disease, Molecular biology, NFE2L2, Endometrial Neoplasms, Nuclear Staining, 030104 developmental biology, Specimen Preparation and Treatment, Tumor Suppressor Protein p53, Gynecological Tumors, Immunostaining |
| الوصف: | Background NRF2 is a major transcription factor regulating the expression of antioxidative/detoxifying enzymes, involved in oncogenic processes and drug resistance. We aimed to identify molecular alterations associated with NRF2 activation in endometrial carcinoma (EC). Methods Ninety patients treated (2012–2017) for localized/locally advanced EC were included in this study. Formalin-fixed paraffin-embedded tissue samples were processed for immunohistochemical (NRF2 and Mismatch Repair proteins) analyses. Next generation sequencing (NGS) of a panel of genes including POLE, TP53, NFE2L2, KEAP1 and CUL3 was performed using Ampliseq panels on Ion Torrent PGM (ThermoFisher). NRF2 activity was assessed by NQO1, GCLC, and AKR1C3 mRNA expressions, using TaqMan assays and quantitative RT-PCR. Results Tumors were classified as POLE exonuclease domain mutated (N = 3, 3%), MMR-deficient (MSI-like) (N = 28, 31%), TP53 mutated (Copy-number high-like) (N = 22, 24%), and other tumors (Copy-number low-like) (N = 32, 36%). NRF2 nuclear immunostaining did not correlate with NRF2 target genes expression. The 3 tumors with highest NRF2 target genes expression harbored oncogenic KEAP1 or NFE2L2 mutations. Low NQO1 mRNA and protein levels were observed in the TP53 mutated subgroup compared to others tumors (p < .05) and in silico analyses of The Cancer Genome Atlas data further indicated that NQO1 mRNA levels were lower in serous compared to endometrioid copy-number high EC. Conclusion In contrast with previous reports based on immunohistochemistry, our study indicates that NRF2 activation is a rare event in EC, associated with NFE2L2 or KEAP1 mutations. The subset of aggressive EC with low NQO1 mRNA level might represent a specific subgroup, which could be sensitive to combination therapies targeting oxidative stress. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ad41b84dd63b8a064fcd881a596ca524Test http://europepmc.org/articles/PMC6433262Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ad41b84dd63b8a064fcd881a596ca524 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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