OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway.
OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway.
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DOI：
10.1038/cddis.2013.272
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发表时间：
2013-08-08
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
八聚体结合转录因子4 （OCT4）是维持胚胎干细胞多能性和自我更新特性的关键调控基因。虽然有新的证据表明它可以在几种癌症中作为致癌基因发挥作用，但在介导宫颈癌中的作用仍未被探索。我们发现OCT4蛋白的表达呈现出从正常宫颈到原位宫颈癌再到浸润性宫颈癌逐渐增加的模式。OCT4在两种宫颈癌细胞中过表达，促进癌变，抑制癌细胞凋亡。OCT4通过直接结合经染色质免疫沉淀分析证实的miR-125b-1启动子诱导miR-125b上调。MiRNA-125b过表达可抑制细胞凋亡和BAK1蛋白的表达。相反，miR-125b海绵抑制OCT4的抗凋亡作用，上调BAK1的表达。值得注意的是，荧光素酶检测显示，野生型BAK1 3 ' -非翻译区报告基因的活性受到抑制，当miR-125b应答元件突变或删除时，这种抑制减弱。此外，我们观察到原发性宫颈癌中BAK1与OCT4水平呈负相关，OCT4与miR-125b水平呈正相关。这些发现提示在宫颈癌中存在一条未被描述的调控途径，OCT4直接诱导miR-125b的表达，从而抑制其直接靶点BAK1，从而抑制宫颈癌细胞凋亡。
Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene that maintains the pluripotency and self-renewal properties of embryonic stem cells. Although there is emerging evidence that it can function as oncogene in several cancers, the role in mediating cervical cancer remains unexplored. Here we found that OCT4 protein expression showed a pattern of gradual increase from normal cervix to cervical carcinoma in situ and then to invasive cervical cancer. Overexpression of OCT4 in two types of cervical cancer cells promotes the carcinogenesis, and inhibits cancer cell apoptosis. OCT4 induces upregulation of miR-125b through directly binding to the promoter of miR-125b-1 confirmed by chromatin immunoprecipitation analysis. MiRNA-125b overexpression suppressed apoptosis and expression of BAK1 protein. In contrast, miR-125b sponge impaired the anti-apoptotic effect of OCT4, along with the upregulated expression of BAK1. Significantly, Luciferase assay showed that the activity of the wild-type BAK1 3′-untranslated region reporter was suppressed and this suppression was diminished when the miR-125b response element was mutated or deleted. In addition, we observed negative correlation between levels of BAK1 and OCT4, and positive between OCT4 and miR-125b in primary cervical cancers. These findings suggest an undescribed regulatory pathway in cervical cancer, by which OCT4 directly induces expression of miR-125b, which inhibits its direct target BAK1, leading to suppression of cervical cancer cell apoptosis.
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影响因子：
2.9
作者：
Kim RJ;Nam JS
通讯作者：
Nam JS
干细胞基因 Oct-4 表达在乳腺癌中的临床意义
影响因子：
9
作者：
Liu, Cai-gang;Lu, Ying;Lu, Ping
通讯作者：
Lu, Ping
影响因子：
6.7
作者：
Chang, Jui-Hung;Au, Heng-Kien;Tzeng, Chii-Ruey
通讯作者：
Tzeng, Chii-Ruey
DOI：
10.1084/jem.20080285
发表时间：
2008-10-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bousquet M;Quelen C;Rosati R;Mansat-De Mas V;La Starza R;Bastard C;Lippert E;Talmant P;Lafage-Pochitaloff M;Leroux D;Gervais C;Viguié F;Lai JL;Terre C;Beverlo B;Sambani C;Hagemeijer A;Marynen P;Delsol G;Dastugue N;Mecucci C;Brousset P
通讯作者：
Brousset P
影响因子：
11.2
作者：
Chang, Chao-Ching;Shieh, Gia-Shing;Wu, Chao-Liang
通讯作者：
Wu, Chao-Liang