NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation.
NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation.
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DOI：
10.1038/onc.2011.114
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发表时间：
2011-09-08
期刊：
影响因子：
8
通讯作者：
Tang, D. G.
中科院分区：
文献类型：
--
作者：
Jeter, C. R.;Liu, B.;Liu, X.;Chen, X.;Liu, C.;Calhoun-Davis, T.;Repass, J.;Zaehres, H.;Shen, J. J.;Tang, D. G.
干细胞（SC）的癌细胞分子模拟使肿瘤细胞具有增强的增殖和更新能力。作为支持，许多SC自我更新的介质已被证明具有致癌潜力。我们最近报道了shRNA介导的胚胎干细胞（ESC）自我更新基因NANOG的敲除显著降低了各种癌细胞的克隆形成和致瘤能力。在这项研究中，我们试图测试NANOG的潜在促肿瘤发生功能，特别是在前列腺癌（PCa）中。使用定量RT-PCR，我们首先证实PCa细胞主要从染色体15 q14上的NANOGP 8位点表达NANOG mRNA。然后，我们构建了慢病毒启动子报告基因，其中约3.8 kb的NANOGP 8基因组片段用于驱动绿色荧光蛋白（GFP）的表达。我们观察到NANOGP 8-GFP+ PCa细胞表现出癌症干细胞（CSC）特征，例如增强的克隆生长和肿瘤再生能力。为了进一步研究NANOG在肿瘤发生中的功能和机制，我们建立了四环素诱导的NANOG过表达癌细胞系，包括前列腺癌（Du 145和LNCaP）和乳腺癌（MCF-7）癌细胞。NANOG诱导促进了MCF-7细胞的耐药性，Du 145细胞的肿瘤再生，最重要的是，LNCaP细胞的去势抵抗性肿瘤发展。NANOG的这些促肿瘤发生作用与关键分子变化相关，包括CXCR 4、IGFBP 5、CD 133和ALDH 1等分子的上调。目前的功能获得的研究，加上我们最近的功能丧失的工作，建立了不可或缺的作用NANOG在肿瘤过程中，并阐明其作用机制。
Cancer cell molecular mimicry of stem cells (SC) imbues neoplastic cells with enhanced proliferative and renewal capacities. In support, numerous mediators of SC self-renewal have been evinced to exhibit oncogenic potential. We have recently reported that shRNA-mediated knockdown of the embryonic stem cell (ESC) self-renewal gene NANOG significantly reduced the clonogenic and tumorigenic capabilities of various cancer cells. In this study, we sought to test the potential pro-tumorigenic functions of NANOG, particularly, in prostate cancer (PCa). Using quantitative RT-PCR, we first confirmed that PCa cells expressed NANOG mRNA primarily from the NANOGP8 locus on chromosome 15q14. We then constructed a lentiviral promoter reporter in which the -3.8 kb NANOGP8 genomic fragment was used to drive the expression of green fluorescence protein (GFP). We observed that NANOGP8-GFP+ PCa cells exhibited cancer stem cell (CSC) characteristics such as enhanced clonal growth and tumor regenerative capacity. To further investigate the functions and mechanisms of NANOG in tumorigenesis, we established tetracycline-inducible NANOG overexpressing cancer cell lines, including both prostate (Du145 and LNCaP) and breast (MCF-7) cancer cells. NANOG induction promoted drug-resistance in MCF-7 cells, tumor regeneration in Du145 cells, and, most importantly, castration-resistant tumor development in LNCaP cells. These pro-tumorigenic effects of NANOG were associated with key molecular changes, including an upregulation of molecules such as CXCR4, IGFBP5, CD133 and ALDH1. The present gain-of-function studies, coupled with our recent loss-of-function work, establish the integral role for NANOG in neoplastic processes and shed light on its mechanisms of action.
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DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
23.9
作者：
Liu Y;Clem B;Zuba-Surma EK;El-Naggar S;Telang S;Jenson AB;Wang Y;Shao H;Ratajczak MZ;Chesney J;Dean DC
通讯作者：
Dean DC
影响因子：
11.2
作者：
Collins, AT;Berry, PA;Maitland, NJ
通讯作者：
Maitland, NJ
影响因子：
11.5
作者：
Chiou, Shih-Hwa;Yu, Cheng-Chia;Lo, Jeng-Fan
通讯作者：
Lo, Jeng-Fan