当前位置: X-MOL 学术Cell Death Differ. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-11-02 , DOI: 10.1038/s41418-020-00651-5
Wenwen Du 1, 2 , Jianjie Zhu 1, 2, 3 , Yuanyuan Zeng 1, 2, 3 , Ting Liu 1, 2 , Yang Zhang 1, 2 , Tingting Cai 1, 2 , Yulong Fu 1, 2 , Weijie Zhang 1, 2 , Ruochen Zhang 1, 2 , Zeyi Liu 1, 2, 3 , Jian-An Huang 1, 2, 3
Affiliation  

In addition to the role of programmed cell death ligand 1 (PD-L1) in facilitating tumour cells escape from immune surveillance, it is considered as a crucial effector in transducing intrinsic signals to promote tumour development. Our previous study has pointed out that PD-L1 promotes non-small cell lung cancer (NSCLC) cell proliferation, but the mechanism remains elusive. Here we first demonstrated that PD-L1 expression levels were positively correlated with p-MerTK levels in patient samples and NSCLC cell lines. In addition, PD-L1 knockdown led to the reduced phosphorylation level of MerTK in vitro. We next showed that PD-L1 regulated NSCLC cell proliferation via Gas6/MerTK signaling pathway in vitro and in vivo. To investigate the underlying mechanism, we unexpectedly found that PD-L1 translocated into the nucleus of cancer cells which was facilitated through the binding of Karyopherin β1 (KPNB1). Nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, regulated the synthesis of Gas6 mRNA and promoted Gas6 secretion to activate MerTK signaling pathway. Taken together, our results shed light on the novel role of nPD-L1 in NSCLC cell proliferation and reveal a new molecular mechanism underlying nPD-L1-mediated Gas6/MerTK signaling activation. All above findings provide the possible combinational implications for PD-L1 targeted immunotherapy in the clinic.



中文翻译:

KPNB1 介导的 PD-L1 核转位通过 Gas6/MerTK 信号通路促进非小细胞肺癌细胞增殖

除了程序性细胞死亡配体 1 (PD-L1) 在促进肿瘤细胞逃避免疫监视方面的作用外,它还被认为是转导内在信号以促进肿瘤发展的关键效应物。我们之前的研究指出,PD-L1 促进非小细胞肺癌 (NSCLC) 细胞增殖,但其机制仍不清楚。在这里,我们首先证明了 PD-L1 表达水平与患者样本和 NSCLC 细胞系中的 p-MerTK 水平呈正相关。此外,PD-L1 敲低导致体外 MerTK 的磷酸化水平降低。我们接下来表明 PD-L1 在体外和体内通过 Gas6/MerTK 信号通路调节 NSCLC 细胞增殖。为了研究潜在的机制,我们意外地发现 PD-L1 易位到癌细胞的细胞核中,这是通过核转运蛋白 β1 (KPNB1) 的结合促进的。核 PD-L1 (nPD-L1) 与转录因子 Sp1 结合,调节 Gas6 mRNA 的合成并促进 Gas6 分泌以激活 MerTK 信号通路。综上所述,我们的结果阐明了 nPD-L1 在 NSCLC 细胞增殖中的新作用,并揭示了 nPD-L1 介导的 Gas6/MerTK 信号激活的新分子机制。所有上述发现为临床上的 PD-L1 靶向免疫治疗提供了可能的组合意义。我们的结果阐明了 nPD-L1 在 NSCLC 细胞增殖中的新作用,并揭示了 nPD-L1 介导的 Gas6/MerTK 信号激活的新分子机制。所有上述发现为临床上的 PD-L1 靶向免疫治疗提供了可能的组合意义。我们的结果阐明了 nPD-L1 在 NSCLC 细胞增殖中的新作用,并揭示了 nPD-L1 介导的 Gas6/MerTK 信号激活的新分子机制。所有上述发现为临床上的 PD-L1 靶向免疫治疗提供了可能的组合意义。

更新日期:2020-11-02
down
wechat
bug