SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells
SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells
复制标题
DOI：
10.1016/j.cellsig.2013.08.041
复制
发表时间：
2013-12-01
影响因子：
4.8
通讯作者：
Tang, Damu
中科院分区：
文献类型：
--
作者：
Rybak, Adrian P.;Tang, Damu
SOX 2是干细胞的重要转录因子，在肿瘤发生中发挥作用，但其在前列腺癌干细胞（PCSC）中的作用尚不清楚。我们在这里报告了一个显着的上调SOX 2在mRNA和蛋白质水平在DU145 PCSCs作为悬浮球在体外繁殖。SOX 2在DU145 PCSCs中的表达受表皮生长因子受体（EGFR）信号正调控。在加入表皮生长因子（EGF）或异位表达组成型活性EGFR突变体（EGFRvIII）后，EGFR信号传导的激活增加了SOX 2表达和DU145 PCSC的自我更新。相反，小分子EGFR抑制剂（AG1478）阻断EGFR活化，减少SOX 2表达并抑制PCSC自我更新活性，暗示SOX 2介导PCSC的EGFR依赖性自我更新。根据这一观点，异位SOX 2表达增强了EGF诱导的DU145 PCSC的自我更新，而SOX 2敲低降低了PCSC的自我更新，EGF处理不再能够增强它们的繁殖。此外，SOX 2敲低降低了DU145 PCSC在锚定非依赖性条件下生长的能力。最后，与源自非PCSC的异种移植肿瘤相比，DU145 PCSC产生的异种移植肿瘤更具侵袭性，SOX 2表达水平升高。总的来说，我们提供的证据表明，SOX 2在EGFR介导的DU145 PCSC自我更新中起着关键作用。(C)2013 Elsevier Inc. All rights reserved.
SOX2 is an essential transcription factor for stem cells and plays a role in tumorigenesis, however its role in prostate cancer stem cells (PCSCs) remains unclear. We report here a significant upregulation of SOX2 at both mRNA and protein levels in DU145 PCSCs propagated as suspension spheres in vitro. The expression of SOX2 in DU145 PCSCs is positively regulated by epidermal growth factor receptor (EGFR) signaling. Activation of EGFR signaling, following the addition of epidermal growth factor (EGF) or ectopic expression of a constitutively-active EGFR mutant (EGFRvIII), increased SOX2 expression and the self-renewal of DU145 PCSCs. Conversely, a small molecule EGFR inhibitor (AG1478) blocked EGFR activation, reduced SOX2 expression and inhibited PCSC self-renewal activity, implicating SOX2 in mediating EGFR-dependent self-renewal of PCSCs. In line with this notion, ectopic SOX2 expression enhanced EGF-induced self-renewal of DU145 PCSCs, while SOX2 knockdown reduced PCSC self-renewal with EGF treatment no longer capable of enhancing their propagation. Furthermore, SOX2 knockdown reduced the capacity of DU145 PCSCs to grow under anchorage-independent conditions. Finally, DU145 PCSCs generated xenograft tumors more aggressively with elevated levels of SOX2 expression compared to xenograft tumors derived from non-PCSCs. Collectively, we provide evidence that SOX2 plays a critical role in EGFR-mediated self-renewal of DU145 PCSCs. (C) 2013 Elsevier Inc. All rights reserved.