KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway.
KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway.
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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
DOI：
10.1038/s41418-020-00651-5
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发表时间：
2021-04
影响因子：
12.4
通讯作者：
Huang JA
中科院分区：
文献类型：
--
作者：
Du W;Zhu J;Zeng Y;Liu T;Zhang Y;Cai T;Fu Y;Zhang W;Zhang R;Liu Z;Huang JA
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中的作用外，它还被认为是传导内在信号以促进肿瘤发展的关键效应物。我们前期研究指出PD-L1促进非小细胞肺癌（NSCLC）细胞增殖，但其机制尚不明确。在这里，我们首次证明了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磷酸化水平降低。在体内和体外实验中，我们发现PD-L1通过Gas6/MerTK信号通路调控NSCLC细胞增殖。为了研究其潜在的机制，我们意外地发现PD-L1通过与核丝蛋白β1 （KPNB1）的结合而转运到癌细胞的细胞核中。核PD-L1 （nPD-L1）与转录因子Sp1结合，调控Gas6 mRNA的合成，促进Gas6的分泌，激活MerTK信号通路。综上所述，我们的研究结果揭示了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。以上结果为临床上PD-L1靶向免疫治疗提供了可能的联合意义。
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.
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影响因子：
7.3
作者：
Geng K;Kumar S;Kimani SG;Kholodovych V;Kasikara C;Mizuno K;Sandiford O;Rameshwar P;Kotenko SV;Birge RB
通讯作者：
Birge RB
影响因子：
8
作者：
Feng, Daofu;Qin, Bo;Sinicrope, Frank A.
通讯作者：
Sinicrope, Frank A.
影响因子：
0.7
作者：
Burstyn-Cohen, Tal
通讯作者：
Burstyn-Cohen, Tal
影响因子：
4.8
作者：
Lee, DK;Suh, D;Hur, MW
通讯作者：
Hur, MW
DOI：
10.1080/21691401.2018.1452022
发表时间：
2018-01-01
影响因子：
5.8
作者：
Eom, Hyojin;Kaushik, Neha;Lee, Su-Jae
通讯作者：
Lee, Su-Jae