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Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis.
Free Radic Biol Med. 2017 09; 110:1-10.FR

Abstract

The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes' transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2-/-) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes.

Authors+Show Affiliations

Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France. Electronic address: louis.marcellin@gmail.com.Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France.Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France.Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France.Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France.Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Service de Chirurgie Digestive, 75679 Paris, France.UMR996 - Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France; Université Paris Sud, INSERM UMR 996, Faculté de Pharmacie, Université Paris-Saclay, Châtenay-Malabry 92290, France.UMR996 - Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France; Université Paris Sud, INSERM UMR 996, Faculté de Pharmacie, Université Paris-Saclay, Châtenay-Malabry 92290, France.Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Service de pathologie, CAncer Research for PErsonalized Medicine (CARPEM), Paris, France.Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France.Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Laboratoire d'Immunologie, 75679 Paris, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28457937

Citation

Marcellin, L, et al. "Alteration of Nrf2 and Glutamate Cysteine Ligase Expression Contribute to Lesions Growth and Fibrogenesis in Ectopic Endometriosis." Free Radical Biology & Medicine, vol. 110, 2017, pp. 1-10.
Marcellin L, Santulli P, Chouzenoux S, et al. Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis. Free Radic Biol Med. 2017;110:1-10.
Marcellin, L., Santulli, P., Chouzenoux, S., Cerles, O., Nicco, C., Dousset, B., Pallardy, M., Kerdine-Römer, S., Just, P. A., Chapron, C., & Batteux, F. (2017). Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis. Free Radical Biology & Medicine, 110, 1-10. https://doi.org/10.1016/j.freeradbiomed.2017.04.362
Marcellin L, et al. Alteration of Nrf2 and Glutamate Cysteine Ligase Expression Contribute to Lesions Growth and Fibrogenesis in Ectopic Endometriosis. Free Radic Biol Med. 2017;110:1-10. PubMed PMID: 28457937.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis. AU - Marcellin,L, AU - Santulli,P, AU - Chouzenoux,S, AU - Cerles,O, AU - Nicco,C, AU - Dousset,B, AU - Pallardy,M, AU - Kerdine-Römer,S, AU - Just,P A, AU - Chapron,C, AU - Batteux,F, Y1 - 2017/04/28/ PY - 2016/11/08/received PY - 2017/04/10/revised PY - 2017/04/19/accepted PY - 2017/5/2/pubmed PY - 2018/4/13/medline PY - 2017/5/2/entrez KW - Endometriosis KW - GCL KW - Nrf2 KW - Oxidative stress SP - 1 EP - 10 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 110 N2 - The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes' transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2-/-) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/28457937/Alteration_of_Nrf2_and_Glutamate_Cysteine_Ligase_expression_contribute_to_lesions_growth_and_fibrogenesis_in_ectopic_endometriosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(17)30550-6 DB - PRIME DP - Unbound Medicine ER -