title: Functional Role of NRF2 in Cervical Carcinogenesis.
abstract: 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.
authors.affiliation: Department of Gynecology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
authors.forename: Jun-Qi
authors.initials: JQ
authors.lastname: Ma
authors.affiliation: Department of Pathology of Medical University of Xinjiang, Urumqi, China.
authors.forename: Hatila
authors.initials: H
authors.lastname: Tuersun
authors.affiliation: Department of Pathology of Medical University of Xinjiang, Urumqi, China.
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Jiao
authors.affiliation: Department of Pathology of Medical University of Xinjiang, Urumqi, China.
authors.forename: Jian-He
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: Department of Gynecology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
authors.forename: Jing-Bao
authors.initials: JB
authors.lastname: Xiao
authors.affiliation: Department of Pathology of Medical University of Xinjiang, Urumqi, China.
authors.forename: Ayshamgul
authors.initials: A
authors.lastname: Hasim
mesh_terms: D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human