Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Oncogene. 2012 Nov 22;31(47):4898-911. doi: 10.1038/onc.2011.656. Epub 2012 Jan 30.
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 sub-population 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 have an important role during tumor progression.
人们对靶向癌症干细胞（CSCs）进行临床治疗非常感兴趣，因为这些细胞具有高度致瘤性并且对化疗有抵抗力。Oct4 在不同类型的癌症中由类似 CSC 的细胞表达。然而，Oct4 在肿瘤细胞中的功能尚不清楚。在这项研究中，我们表明 Oct4 基因的表达或 Oct4 蛋白的跨膜传递促进了黑色素瘤细胞向 CSC 样细胞的去分化。去分化的黑色素瘤细胞表现出黑色素细胞标志物的表达显著降低，并获得了形成肿瘤球的能力。它们对化疗药物和缺氧损伤的抵抗力明显增加。在皮下异种移植和尾静脉注射实验中，这些细胞的致瘤能力显著增加。去分化的黑色素瘤细胞获得了与 CSCs 相关的特征，例如多能分化能力和黑色素瘤 CSC 标志物 ABCB5 和 CD271 的表达。从机制上讲，Oct4 诱导的去分化与内源性 Oct4、Nanog 和 Klf4 的表达增加以及富含转录因子的全基因组表达变化有关。在去分化细胞中用 RNAi 敲低 Oct4 导致 CSC 表型减弱。黑色素瘤中的 Oct4 表达受缺氧调节，并在临床样本中的黑色素瘤细胞亚群中检测到。我们的数据表明 Oct4 是肿瘤去分化的正向调节剂。结果表明，CSC 表型是动态的，可能通过去分化获得。Oct4 介导的肿瘤细胞去分化在肿瘤进展过程中可能具有重要作用。
