The NRF2 transcriptional target NQO1 has low mRNA levels in TP53-mutated endometrial carcinomas.
Adult
Aged
Aged, 80 and over
Endometrial Neoplasms
/ diagnosis
Female
Gene Expression Regulation, Neoplastic
Humans
Kelch-Like ECH-Associated Protein 1
/ genetics
Middle Aged
Mutation
NAD(P)H Dehydrogenase (Quinone)
/ genetics
NF-E2-Related Factor 2
/ genetics
Prognosis
RNA, Messenger
/ genetics
Transcription, Genetic
Tumor Suppressor Protein p53
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
07
12
2018
accepted:
12
03
2019
entrez:
26
3
2019
pubmed:
26
3
2019
medline:
18
12
2019
Statut:
epublish
Résumé
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). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30908539
doi: 10.1371/journal.pone.0214416
pii: PONE-D-18-35071
pmc: PMC6433262
doi:
Substances chimiques
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
RNA, Messenger
0
Tumor Suppressor Protein p53
0
NAD(P)H Dehydrogenase (Quinone)
EC 1.6.5.2
NQO1 protein, human
EC 1.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0214416Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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