Abstract
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.
Highlights
Pap screen testing and early detection have dramatically increased survival rates, cervical cancer remains the second leading cause of cancer-related mortality among women worldwide.[1]
octamer-binding transcription factor 4 (OCT4)-positive cells were found in 35.71% (15/42) of NC samples, 75.00% (15/20) of cervical carcinoma in situ (CIS) samples and 88.64% (39/44) of invasive cervical carcinoma samples (Figure 1b)
MiR-125b sponge restored the depression of apoptosis by OCT4 overexpression. These results indicate that HeLa cell apoptosis was negatively correlated with miR-125b expression, and inactivation of miR-125b can abolish the effect induced by OCT4
Summary
Pap screen testing and early detection have dramatically increased survival rates, cervical cancer remains the second leading cause of cancer-related mortality among women worldwide.[1]. OCT4 is a nuclear transcription factor of the POUhomeodomain family that has a critical role in several aspects of embryonic stem cell (ESC) maintenance, including ESC self-renewal, pluripotency and lineage commitment.[6,7,8] Changes in OCT4 expression are involved in numerous developmental programs. A transient increase in OCT4 levels can induce lineage commitment to the primitive endoderm and mesoderm, whereas repression of OCT4 leads to trophectoderm differentiation.[9,10] At the top of the pluripotent cell genetic regulatory network, OCT4 and SOX2 work cooperatively to stimulate the transcription of several target genes, including
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