Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3.
Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3.
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DOI：
10.1016/j.canlet.2021.12.017
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发表时间：
2021-12
期刊：
影响因子：
9.7
通讯作者：
Rui Ma;Yunpeng Liu;X. Che;Ce Li;T. Wen;K. Hou;X. Qu
中科院分区：
文献类型：
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作者：
Rui Ma;Yunpeng Liu;X. Che;Ce Li;T. Wen;K. Hou;X. Qu
具有BRAFV 600 E突变的结直肠癌（CRC）表现出程序性死亡配体1（PD-L1）的上调，但对靶向程序性细胞死亡蛋白1（PD-1）/PD-L1的免疫治疗无效。最近的研究已经探索了PD-L1的细胞内功能。在这里，我们证明PD-L1在BRAF突变的CRC肿瘤细胞和组织的细胞质和细胞核中高度表达。核PD-L1（nPD-L1）在体外和体内均能促进肿瘤细胞的生长。机制研究表明，PD-L1易位到细胞核是由p-ERK的结合促进的。此外，nPD-L1通过与甲状腺激素受体相关蛋白3（THRAP 3）的相互作用上调细胞周期调节因子BUB 1的表达，从而加速细胞周期进程并促进细胞增殖。此外，BRAFV 600 E突变的CRC细胞表现出通过转录因子LEF-1上调PD-L1表达。这些发现揭示了nPD-L1的一种新作用，它在BRAFV 600 E突变的CRC中以免疫非依赖性方式促进细胞周期进展。我们的研究为BRAFV 600 E突变的CRC进展机制提供了新的见解。
Colorectal cancers (CRCs) with theBRAFV600E mutation exhibit upregulation of programmed death ligand 1 (PD-L1) but fail to respond to immunotherapy targeting programmed cell death protein 1 (PD-1)/PD-L1. Recent studies have explored the intracellular functions of PD-L1. Here, we demonstrate that PD-L1 was highly expressed in both the cytoplasm and nucleus ofBRAF-mutated CRC tumor cells and tissues. Nuclear PD-L1 (nPD-L1) promoted the growth of tumor cells bothin vitroandin vivo. Mechanistic investigations revealed that PD-L1 translocation into the nucleus was facilitated by the binding ofp-ERK. Further, nPD-L1 upregulated the expression of cell cycle regulator BUB1 via interactions with thyroid hormone receptor-associated protein 3 (THRAP3), thereby accelerating cell cycle progression and promoting cell proliferation. Moreover,BRAFV600E-mutated CRC cells exhibited upregulation of PD-L1 expression via the transcription factor LEF-1. These findings reveal a novel role of nPD-L1, which promotes cell cycle progression in an immune-independent manner inBRAFV600E-mutated CRC. Our study provides novel insight into the mechanisms underlyingBRAFV600E-mutated CRC progression.