Functional Role of NRF2 in Cervical Carcinogenesis.
Functional Role of NRF2 in Cervical Carcinogenesis.
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NRF2 在宫颈癌发生中的功能作用
DOI：
10.1371/journal.pone.0133876
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hasim A
中科院分区：
文献类型：
--
作者：
Ma JQ;Tuersun H;Jiao SJ;Zheng JH;Xiao JB;Hasim A
核因子红细胞-2相关因子2（NFE 2L 2）是一种与化疗耐药性和肿瘤生长增加相关的转录因子。NRF 2被抑制剂Keap 1抑制。Keap 1-NRF 2通路在多种肿瘤类型中功能失调。在维吾尔族妇女中，宫颈鳞状细胞癌（CSCC）和宫颈上皮内瘤变（CIN）的发病率与NRF 2的核表达升高和Keap 1的胞浆表达降低相关。核NRF 2的上调与细胞质Keap 1表达的降低显著相关。NRF 2阳性和Keap 1阴性通常与更晚期的肿瘤相关（即，较高的组织学分级、淋巴结受累和较高的肿瘤分期）（全部P<0.05）。使用MassARRAY鉴定宫颈癌组织中Keap 1基因启动子中的甲基化CpG岛。此外，该基因的启动子甲基化与宫颈癌组织中蛋白表达降低和核NRF 2表达增加显著相关。NRF 2在CSCC细胞系中的过表达和敲低表明NRF 2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Keap 1表达的概念。NRF 2表达与侵袭性肿瘤行为的相关性表明，NRF 2可能是宫颈癌患者预后不良的标志物。
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.