The Role and Specific Mechanism of OCT4 in Cancer Stem Cells: A Review.

Cancer stem cells (CSCs) are a type of cell population with self-renewal and replication that have been found to be the origin of cancer ( 1 , 2 ). Growing evidence indicates that CSCs are tumor-initiating cells and play a non-negligible role in cancer recurrence, metastasis, and drug resistance ( 1 , 3 , 4 ). However, it is unclear how CSCs are generated and maintain stemness, which make tumor treatment challenging. Octamer-binding transcription factor 4 (OCT4), which is encoded by the Pou5f1 gene and is a member of the POU-domain transcription factor family, is connected to maintain pluripotency of embryonic stem cells (ESCs) and CSCs ( 5 - 7 ). Mouse Oct4 has two homologs, Oct4A and Oct4B, the former in the nucleus and the latter in the cytoplasm ( 8 ). Unlike mice, human OCT4 has three homologs, OCT4A, OCT4B and OCT4B1 ( 9 ). One study found that Oct4 expression was not detectable in adult murine organs ( 10 ). Meanwhile, some researchers also suggested that although Oct4 expression cannot be detected in testes, brain, liver, lung, kidney, and intestine, there is Oct4 expression in primordial germ cells and unfertilized oocytes, which shows that differential regulation of Oct4 expre-ssion during mouse development ( 11 ). However, a study has found that there is Oct4 mRNA expression in the murine adult ovaries and testes, especially mature and ovulating oocytes rather than resting oocytes, which may be due to Oct4 transactivate genes that are important for oocyte maturation ( 12 ). Gradually, some researchers suggest that Oct4 is necessary and sufficient to induce pluripotency of adult mouse neural stem cells ( 13 ). The expression of OCT4 in several human adult stem cells, such as breast, pancreatic, and liver stem cells, supports the hypothesis that stem cells are carcinogenic target cells ( 14 ). Additionally, OCT4 may generate resistance to radiotherapy by improving the epithelial to mesenchymal transition (EMT) process in human rectal cancer cells, and OCT4 is closely related to DNA damage when cancer cells respond to radiotherapy ( 15 ). Studies also indicate that OCT4 is strongly associated with tumor invasion and migration and can lead to poor prognosis for patients ( 6 ). Unfortunately, studies on the functions and mechanisms of OCT4 in the production of CSCs are scarce. The purpose of this review is to summarize the relationship between OCT4 and CSCs to provide possibilities for clinical treatment by exploring targets related to OCT4.

The role of OCT4 in pluripotency maintenance makes OCT4 a new cancer treatment target. Increased experiments have found that siRNA targeting OCT4 induces apoptosis, inhibits proliferation, EMT, and drug resistance in pancreatic cancer cells and head and neck squamous cell carcinoma CSCs, breast CSCs ( 66 - 68 ). Similar results have been found in lung cancer, ovarian cancer, liver cancer, and glioma ( 37 , 106 ). However, an experiment suggested that OCT4 knockout in the MCF-7 human breast cancer cell line induced cell invasion, migration, and EMT, which is because MCF-7 cells already have high expression of OCT4 ( 37 , 132 ). Moreover, due to the intra- and extracellular degradation of enzymes, the delivery efficiency of siRNA is limited, which still needs to be solved ( 66 ). The epigenetic regulator JMJD3 inhibits OCT4 expression in human breast cancer cells in an independent manner with demethylase activity, and paricalcitol, a vitamin D analog, inhibits OCT4 expression and stem cell-like characteristics of human breast cancer cells after promoting JMJD3 expression ( 133 ). Recently, three different Oct4 epitopes were chemically synthesized, among which Oct4-3 and carrier protein KLH induced a strong tumor-specific adaptive immune response in combination with toll-like receptor 9 agonist, thereby inhibiting mouse testis embryonic carcinoma growth and promoting long-term survival. Importantly, the mice were well tolerated with the Oct4-3 vaccine and no obvious adverse events were observed ( 134 ). Additionally, targeting upstream activators of OCT4 is also a new method. For instance, the use of Notch pathway inhibitor L685,458 can reduce the expression of OCT4 and reverse stem cell-like phenotype and resistance to paclitaxel of breast cancer cells ( 19 , 135 ). Using siRNA to target OCT4B1 induces apoptosis or G2/M arrest in human brain cancer cells, suggesting that OCT4B1 may also be a potential therapeutic target in brain cancer ( 136 ).

CSCs are a group of cells with the ability to self-renew and differentiate among cancer cells. Their discovery provides the possibility to solve tumor recurrence, metastasis and resistance. OCT4 as a stem transcription factor is widely expressed in ESCs and CSCs, and research has found that OCT4 may participate in the regulation of CSCs through various forms, but the specific mechanism may not be clear. This review mainly proposes the specific role of OCT4 in CSCs from the epigenetic modification of OCT4 and complexes, non-coding RNA and signaling pathways related to OCT4, which may provide multiple targets for the treatment of CSCs to achieve the purpose of extending patient life.