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Functional Role of NRF2 in Cervical Carcinogenesis

Nuclear factor erythroid-2-related factor 2 (NFE2L2) is a transcription factor associated with resistance to chemotherapy and increased tumor growth. NRF2 is repressed by the inhibitor Keap1. The Keap1-NRF2 pathway is dysfunctional in multiple tumor types. Among Uighur women, the incidence of cervic...

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Autores principales: Ma, Jun-Qi, Tuersun, Hatila, Jiao, Shu-Juan, Zheng, Jian-He, xiao, Jing-Bao, Hasim, Ayshamgul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527737/
https://www.ncbi.nlm.nih.gov/pubmed/26247201
http://dx.doi.org/10.1371/journal.pone.0133876
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author Ma, Jun-Qi
Tuersun, Hatila
Jiao, Shu-Juan
Zheng, Jian-He
xiao, Jing-Bao
Hasim, Ayshamgul
author_facet Ma, Jun-Qi
Tuersun, Hatila
Jiao, Shu-Juan
Zheng, Jian-He
xiao, Jing-Bao
Hasim, Ayshamgul
author_sort Ma, Jun-Qi
collection PubMed
description Nuclear factor erythroid-2-related factor 2 (NFE2L2) is a transcription factor associated with resistance to chemotherapy and increased tumor growth. NRF2 is repressed by the inhibitor Keap1. The Keap1-NRF2 pathway is dysfunctional in multiple tumor types. Among Uighur women, the incidence of cervical squamous cell carcinoma (CSCC) and cervical intraepithelial neoplasia (CIN) was associated with elevated nuclear expression of NRF2 and decreased cytoplasmic expression of Keap1. Up-regulation of nuclear NRF2 was significantly associated with reduced cytoplasmic Keap1 expression. NRF2 positivity and Keap1 negativity were frequently associated with more advanced tumors (i.e., higher histological grade, lymph node involvement, and higher tumor stages) (p<0.05 for all). Methylated CpG islands in the Keap1 gene promoter in cervical cancer tissue were identified using MassARRAY. Moreover, promoter hypermethylation of this gene was significantly associated with decreased protein expression and increased nuclear NRF2 expression in cervical cancer tissues. Overexpression and knockdown of NRF2 in CSCC cell lines showed that NRF2 promotes proliferation, inhibits apoptosis, and enhances migration and invasion. These studies support the concept that epigenetic changes regulate expression of Keap1 in cervical cancer tissues. The association of NRF2 expression with aggressive tumor behavior suggests that NRF2 may be a marker of poor prognosis in patients with cervical cancer.
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spelling pubmed-45277372015-08-12 Functional Role of NRF2 in Cervical Carcinogenesis Ma, Jun-Qi Tuersun, Hatila Jiao, Shu-Juan Zheng, Jian-He xiao, Jing-Bao Hasim, Ayshamgul PLoS One Research Article Nuclear factor erythroid-2-related factor 2 (NFE2L2) is a transcription factor associated with resistance to chemotherapy and increased tumor growth. NRF2 is repressed by the inhibitor Keap1. The Keap1-NRF2 pathway is dysfunctional in multiple tumor types. Among Uighur women, the incidence of cervical squamous cell carcinoma (CSCC) and cervical intraepithelial neoplasia (CIN) was associated with elevated nuclear expression of NRF2 and decreased cytoplasmic expression of Keap1. Up-regulation of nuclear NRF2 was significantly associated with reduced cytoplasmic Keap1 expression. NRF2 positivity and Keap1 negativity were frequently associated with more advanced tumors (i.e., higher histological grade, lymph node involvement, and higher tumor stages) (p<0.05 for all). Methylated CpG islands in the Keap1 gene promoter in cervical cancer tissue were identified using MassARRAY. Moreover, promoter hypermethylation of this gene was significantly associated with decreased protein expression and increased nuclear NRF2 expression in cervical cancer tissues. Overexpression and knockdown of NRF2 in CSCC cell lines showed that NRF2 promotes proliferation, inhibits apoptosis, and enhances migration and invasion. These studies support the concept that epigenetic changes regulate expression of Keap1 in cervical cancer tissues. The association of NRF2 expression with aggressive tumor behavior suggests that NRF2 may be a marker of poor prognosis in patients with cervical cancer. Public Library of Science 2015-08-06 /pmc/articles/PMC4527737/ /pubmed/26247201 http://dx.doi.org/10.1371/journal.pone.0133876 Text en © 2015 Ma et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ma, Jun-Qi
Tuersun, Hatila
Jiao, Shu-Juan
Zheng, Jian-He
xiao, Jing-Bao
Hasim, Ayshamgul
Functional Role of NRF2 in Cervical Carcinogenesis
title Functional Role of NRF2 in Cervical Carcinogenesis
title_full Functional Role of NRF2 in Cervical Carcinogenesis
title_fullStr Functional Role of NRF2 in Cervical Carcinogenesis
title_full_unstemmed Functional Role of NRF2 in Cervical Carcinogenesis
title_short Functional Role of NRF2 in Cervical Carcinogenesis
title_sort functional role of nrf2 in cervical carcinogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527737/
https://www.ncbi.nlm.nih.gov/pubmed/26247201
http://dx.doi.org/10.1371/journal.pone.0133876
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