Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation.
Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation.
复制标题
DOI：
10.1038/onc.2011.656
复制
发表时间：
2012-11-22
期刊：
影响因子：
8
通讯作者：
Xu, X.
中科院分区：
文献类型：
--
作者：
Kumar, S. M.;Liu, S.;Lu, H.;Zhang, H.;Zhang, P. J.;Gimotty, P. A.;Guerra, M.;Guo, W.;Xu, X.
人们对靶向癌症干细胞（CSC）进行临床治疗产生了巨大的兴趣，因为这些细胞具有高度致瘤性且对化疗具有耐药性。Oct4由不同类型癌症中的CSC样细胞表达。然而，Oct4在肿瘤细胞中的功能尚不清楚。在这项研究中，我们发现Oct4基因的表达或Oct4蛋白的跨膜递送促进黑色素瘤细胞向CSC样细胞的去分化。去分化的黑色素瘤细胞表现出黑素细胞标志物的表达显著降低，并获得形成肿瘤球体的能力。他们表现出显着增加耐化疗药物和缺氧损伤。在皮下异种移植和尾静脉注射试验中，这些细胞具有显著增加的致瘤能力。去分化的黑色素瘤细胞获得与CSC相关的特征，例如多能分化能力和黑色素瘤CSC标志物（例如ABCB 5和CD 271）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局基因表达变化相关。RNAi介导的Oct4在去分化细胞中的敲低导致CSC表型减少。Oct4在黑色素瘤中的表达受缺氧调节，并且在临床样品中的黑色素瘤细胞亚群中检测到其表达。我们的数据表明Oct4是肿瘤去分化的正调节因子。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可能在肿瘤进展中起重要作用。
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.
登录
查看更多内容
影响因子：
11.5
作者：
Magnifico, Alessandra;Albano, Luisa;Tagliabue, Elda
通讯作者：
Tagliabue, Elda
影响因子：
8.4
作者：
Monzani, Elena;Facchetti, Floriana;La Porta, Caterina A. M.
通讯作者：
La Porta, Caterina A. M.
影响因子：
64.8
作者：
Kim, Jeong Beom;Greber, Boris;Schoeler, Hans R.
通讯作者：
Schoeler, Hans R.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.102660199
发表时间：
2002-05-14
影响因子：
11.1
作者：
Jögi, A;Ora, I;Påhlman, S
通讯作者：
Påhlman, S