Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation

Abstract

There is enormous interest to target cancer stem cells (CSCs) for clinical treatment because these cells are highly tumorigenic and resistant to chemotherapy. Oct4 is expressed by CSC-like cells in different types of cancer. However, function of Oct4 in tumor cells is unclear. In this study, we showed that expression of Oct4 gene or transmembrane delivery of Oct4 protein promoted dedifferentiation of melanoma cells to CSC-like cells. The dedifferentiated melanoma cells showed significantly decreased expression of melanocytic markers and acquired the ability to form tumor spheroids. They showed markedly increased resistance to chemotherapeutic agents and hypoxic injury. In the subcutaneous xenograft and tail vein injection assays, these cells had significantly increased tumorigenic capacity. The dedifferentiated melanoma cells acquired features associated with CSCs such as multipotent differentiation capacity and expression of melanoma CSC markers such as ABCB5 and CD271. Mechanistically, Oct4 induced dedifferentiation was associated with increased expression of endogenous Oct4, Nanog and Klf4, and global gene expression changes that enriched for transcription factors. RNAi mediated knockdown of Oct4 in dedifferentiated cells led to diminished CSC phenotypes. Oct4 expression in melanoma was regulated by hypoxia and its expression was detected in a subpopulation of melanoma cells in clinical samples. Our data indicate that Oct4 is a positive regulator of tumor dedifferentiation. The results suggest that CSC phenotype is dynamic and may be acquired through dedifferentiation. Oct4 mediated tumor cell dedifferentiation may play an important role during tumor progression.

A Novel Small-Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance

“…For example, Sox2 overexpression increases mammosphere formation, whereas the suppression of Sox2 suppresses mammosphere formation and delays tumor progression in xenograft tumor initiation models (32). In addition, the overexpression of Oct4 promotes the dedifferentiation of melanoma cells to tumor-initiating-like cells, whereas the knockdown of Oct4 in dedifferentiated cells lead to a loss of TIC phenotypes (31). Moreover, Nanog regulates selfrenewal of TICs through the insulin-like growth factor pathway in human hepatocellular carcinoma (33).…”

“…The kinase activity of AurA was significantly increased in MCF-7-Epi cells compared with wild-type MCF-7 cells, suggesting that AurA kinase activity might be important for maintaining resistance to epirubicin. Self-renewal genes, including b-catenin, c-Myc, Sox2, Oct4, and Nanog, play key roles in maintaining stemness (26)(27)(28)(29)(30)(31)(32)(33) and mediating chemoresistance (34)(35)(36). As shown in Fig.…”

RRAD Promotes EGFR-Mediated STAT3 Activation and Induces Temozolomide Resistance of Malignant Glioblastoma

“…Expression of the stem cell transcription factors, OCT4, SOX2, and NANOG decreased with the decrease in RRAD levels, suggesting a tight correlation between RRAD levels and self-renewal processes. OCT4, upregulated by RRAD, is responsible for the maintenance of stem cells (40,41). Thus, RRAD-induced STAT3 activation and OCT4 expression may facilitate the maintenance of GBM cells in a stemlike state and contribute to EMT transition of GBM.…”

Upregulation of microRNA-200a associates with tumor proliferation, CSCs phenotype and chemosensitivity in ovarian cancer

“…Additionally, the tendency of suspended SDCs re-adhere to the plate surface was observed following the over-expression of miR-200a. Generally, SDCs enriched with poorly differentiated CSCs would remain suspended in serum-free medium [13]. Furthermore, overexpression of miR-200a significantly reduced the proportion of SP cells.…”