Ma Jun-Qi, Tuersun Hatila, Jiao Shu-Juan, Zheng Jian-He, Xiao Jing-Bao, Hasim Ayshamgul
Department of Gynecology, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Department of Pathology of Medical University of Xinjiang, Urumqi, China.
PLoS One. 2015 Aug 6;10(8):e0133876. doi: 10.1371/journal.pone.0133876. eCollection 2015.
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.
核因子红细胞2相关因子2（NFE2L2）是一种与化疗耐药性和肿瘤生长增加相关的转录因子。NRF2被抑制剂Keap1所抑制。Keap1-NRF2通路在多种肿瘤类型中功能失调。在维吾尔族女性中，宫颈鳞状细胞癌（CSCC）和宫颈上皮内瘤变（CIN）的发生率与NRF2核表达升高和Keap1胞质表达降低有关。核NRF2的上调与胞质Keap1表达降低显著相关。NRF2阳性和Keap1阴性常与更晚期肿瘤相关（即更高的组织学分级、淋巴结受累和更高的肿瘤分期）（所有p<0.05）。使用MassARRAY鉴定了宫颈癌组织中Keap1基因启动子的甲基化CpG岛。此外，该基因的启动子高甲基化与宫颈癌组织中蛋白表达降低和核NRF2表达增加显著相关。在CSCC细胞系中过表达和敲低NRF2表明，NRF2促进增殖、抑制凋亡并增强迁移和侵袭。这些研究支持了表观遗传变化调节宫颈癌组织中Keap1表达的概念。NRF2表达与侵袭性肿瘤行为的关联表明，NRF2可能是宫颈癌患者预后不良的标志物。
