PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation.
PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation.
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PD-L1通过维持PI3K/AKT途径激活来促进乳腺癌干细胞中的Oct4和Nanog表达。
DOI：
10.1002/ijc.30834
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发表时间：
2017-10-01
影响因子：
6.4
通讯作者：
Ghebeh H
中科院分区：
文献类型：
--
作者：
Almozyan S;Colak D;Mansour F;Alaiya A;Al-Harazi O;Qattan A;Al-Mohanna F;Al-Alwan M;Ghebeh H
PD-L1在乳腺癌中的表达与雌激素受体阴性、化疗耐药性和上皮间质转化（EMT）相关，所有这些都是称为癌症干细胞（CSC）的高度致瘤性癌细胞亚群的共同特征。然而，尚未研究PD-L1在乳腺CSC动力学中的表达和内在作用。为了解决这个问题，我们使用了转录组数据集，蛋白质组学和几种体外和体内测定。大型乳腺癌数据集（530例患者）的表达谱显示，PD-L1表达与乳腺癌干性评分之间存在统计学显著相关性（p < 0.0001，r = 0.36）。使用shRNA特异性敲除PD-L1揭示了其在胚胎干细胞转录因子OCT-4A、Nanog和干细胞因子BMI 1表达中的关键作用。相反，这些因子可以在正常PD-L1阴性的细胞中PD-L1异位表达时诱导。全球蛋白质组学分析暗示了AKT在PD-L1表达细胞的生物学中的核心作用。事实上，PD-L1对OCT-4A和Nanog的积极作用依赖于AKT激活。最重要的是，PD-L1的下调会损害体外和体内乳腺CSC的自我更新能力，分别如肿瘤球形成试验和极限稀释试验所示。这项研究证明了PD-L1在维持乳腺癌细胞干细胞性方面的新作用，并确定了抗PD-L1治疗靶向的亚群及其相关分子途径。 有什么新消息吗？ 表达T细胞抑制分子程序性死亡配体1（PD-L1）的癌细胞很容易逃脱免疫攻击。此外，PD-L1表达有助于化疗耐药性，并与上皮向间充质转化有关，这是一个产生癌症干细胞（CSC）的过程。这项研究表明，在乳腺癌中，PD-L1表达进一步在维持CSC干性中发挥直接作用。在乳腺癌细胞中，PD-L1表达通过PI 3 K/AKT依赖性途径维持干性因子OCT-4A和Nanog，并促进干性控制因子BMI 1的表达，而不依赖于PI 3 K/AKT。靶向PD-L1可能有助于推进乳腺癌治疗，因为它会影响乳腺CSC的数量。
The expression of PD‐L1 in breast cancer is associated with estrogen receptor negativity, chemoresistance and epithelial‐to‐mesenchymal transition (EMT), all of which are common features of a highly tumorigenic subpopulation of cancer cells termed cancer stem cells (CSCs). Hitherto, the expression and intrinsic role of PD‐L1 in the dynamics of breast CSCs has not been investigated. To address this issue, we used transcriptomic datasets, proteomics and several in vitro and in vivo assays. Expression profiling of a large breast cancer dataset (530 patients) showed statistically significant correlation (p < 0.0001, r = 0.36) between PD‐L1 expression and stemness score of breast cancer. Specific knockdown of PD‐L1 using ShRNA revealed its critical role in the expression of the embryonic stem cell transcriptional factors: OCT‐4A, Nanog and the stemness factor, BMI1. Conversely, these factors could be induced upon PD‐L1 ectopic expression in cells that are normally PD‐L1 negative. Global proteomic analysis hinted for the central role of AKT in the biology of PD‐L1 expressing cells. Indeed, PD‐L1 positive effect on OCT‐4A and Nanog was dependent on AKT activation. Most importantly, downregulation of PD‐L1 compromised the self‐renewal capability of breast CSCs in vitro and in vivo as shown by tumorsphere formation assay and extreme limiting dilution assay, respectively. This study demonstrates a novel role for PD‐L1 in sustaining stemness of breast cancer cells and identifies the subpopulation and its associated molecular pathways that would be targeted upon anti‐PD‐L1 therapy. What's new? Cancer cells that express the T‐cell inhibitory molecule programmed death‐ligand 1 (PD‐L1) readily escape immune attack. In addition, PD‐L1 expression contributes to chemoresistance and is associated with epithelial‐to‐mesenchymal transition, a process that generates cancer stem cells (CSCs). This study shows that in breast cancer, PD‐L1 expression further plays a direct part in maintaining CSC stemness. In breast cancer cells, PD‐L1 expression sustained stemness factors OCT‐4A and Nanog, via a PI3K/AKT‐dependent pathway, and promoted expression of the stemness controlling factor BMI1, independent of PI3K/AKT. Targeting PD‐L1 could help advance breast cancer therapy, owing to impacts on the pool of breast CSCs.
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影响因子：
3.8
作者：
Ghebeh H;Sleiman GM;Manogaran PS;Al-Mazrou A;Barhoush E;Al-Mohanna FH;Tulbah A;Al-Faqeeh K;Adra CN
通讯作者：
Adra CN
影响因子：
16
作者：
Lin, Yuanji;Yang, Ying;Li, Weihua;Chen, Qi;Li, Jie;Pan, Xiao;Zhou, Lina;Liu, Changwei;Chen, Chunsong;He, Jianqin;Cao, Hongcui;Yao, Hangping;Zheng, Li;Xu, Xiaowei;Xia, Zongping;Ren, Jiangtao;Xiao, Lei;Li, Lanjuan;Shen, Binghui;Zhou, Honglin;Wang, Ying-Jie
通讯作者：
Wang, Ying-Jie
影响因子：
3.7
作者：
Al-Alwan M;Olabi S;Ghebeh H;Barhoush E;Tulbah A;Al-Tweigeri T;Ajarim D;Adra C
通讯作者：
Adra C
影响因子：
158.5
作者：
Robert, Caroline;Schachter, Jacob;Ribas, Antoni
通讯作者：
Ribas, Antoni
影响因子：
10.3
作者：
Werzowa, J.;Cejka, D.;Pratscher, B.
通讯作者：
Pratscher, B.