OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway.
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.
Department of Reproductive Medicine, First Affiliated Hospital, Xi'an Jiaotong University of Medical School, Xi'an, People's Republic of China.
Y-D
YD
Wang
N
N
Cai
X-L
XL
Wu
H-Z
HZ
Cao
L-L
LL
Xie
P-S
PS
Zheng
D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000473:pathology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism / Q000502:physiology*
C494772:BAK1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein