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Stem Cells:科学家揭开抑制肺癌干细胞活性的分子机制

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 肺癌是常见的第二大癌症,而且其也是引发患者癌症相关死亡的主要原因,据估计在美国每年大约有15.8万人死于肺癌;很多科学家们都认为靶向作用肺癌干细胞或许可以完全清除肺癌组织,而近日一篇发表于国际杂志Stem Cells上的研究论文中,来自Moffitt癌症研究中心的研究者揭示了一种新型机制,其或许在肺癌干细胞的维持过程中扮演着重要角色。

  肺癌是常见的第二大癌症,而且其也是引发患者癌症相关死亡的主要原因,据估计在美国每年大约有15.8万人死于肺癌;很多科学家们都认为靶向作用肺癌干细胞或许可以完全清除肺癌组织,而近日一篇发表于国际杂志Stem Cells上的研究论文中,来自Moffitt癌症研究中心的研究者揭示了一种新型机制,其或许在肺癌干细胞的维持过程中扮演着重要角色。
  癌症干细胞是肿瘤中的一组细胞,其被认为可以开启癌症的复发,而其也可以通过自我更新来复制癌细胞,并且维持肿瘤的生长;研究者表示,这些干细胞同时也会促进癌症的转移,从而使得机体中的癌细胞难以清除。一种名为YAP1的蛋白此前被认为可以促进肺癌细胞的生长,然而研究者并不清楚YAP1如何控制肺癌的生长及进展,本文中研究者就发现YAP1在癌症干细胞的自我更新中扮演着重要的作用。
  YAP1在肺癌干细胞中水平较高,其可以结合一种名为OCT4的蛋白质,两者结合后会调节第三种蛋白—SOX2,这种精细化调节就会促进干细胞维持其自我更新及形成血管样结构的能力。研究者在肺癌组织和正常组织中对比了YAP1和OCT4的水平,结果显示,相比正常组织而言,YAP1在原发性和转移性的肺部肿瘤组织中可以以高水平存在,并且同OCT4相互作用,另外肿瘤中YAP1处于高水平的肺癌病人更易于有较差的预后(相比YAP1水平较低患者),研究者发现YAP1或许可以作为一种潜在的治疗靶点。
  随后研究者研究发现,如果阻断YAP1就可以抑制肺癌干细胞进行自我更新及形成血管样结构,进而减少小鼠机体中肺癌细胞的生长;本文研究揭示,YAP1的抑制子或阻断YAP1同OCT4相互作用的制剂或许就具有一定的抗癌效应,而YAP1新型有效抑制子的鉴别或许也可以帮助科学家们开发出靶向杀灭肺癌干细胞及治疗肺癌的抗癌制剂。(转化医学网360zhyx.com)
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转化医学网推荐的原文摘要:

YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate self-renewal and Vascular Mimicry of Stem-like Cells
STEM CELLS    DOI: 10.1002/stem.1993
Namrata Bora-Singhal1, Jonathan Nguyen1, Courtney Schaal1, Deepak Perumal†, Sandeep Singh‡, Domenico Coppola2 andSrikumar Chellappan1,*
Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem-like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional co-activator YAP1, which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce Sox2 through a physical interaction with Oct4; Sox2 induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem-like cells disrupted the interaction and abrogated Sox2 expression, self-renewal and vascular mimicry. Depleting YAP1 reduced the expression of multiple EMT genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem-like functions by YAP1, through the modulation of Sox2 expression. This article is protected by copyright. All rights reserved.

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