细胞生长
癌症研究
转移
基因沉默
T细胞
癌细胞
细胞生物学
生物
癌变
化学
细胞
效应器
下调和上调
信号转导
免疫系统
癌症
免疫学
生物化学
基因
遗传学
作者
Qian Wu,Yingjie Xu,Xujun Li,Huina Liu,Tianzi You,Ting Cai,Fan Yang
标识
DOI:10.1016/j.biocel.2022.106314
摘要
Programmed cell death 1 (PD-1) suppresses T effector functions by inhibiting signaling downstream of the T cell receptor and helping tumor cells escape the immune response. However, the effect and mechanism of cell-intrinsic PD-1 in cancer cells are still unknown. Here, we found that PD-1 is aberrantly upregulated in TNBC patients and cell lines. Cell-intrinsic PD-1 in TNBC cells significantly facilitated tumor growth and metastasis in vitro and in vivo. Further studies indicated that PD-1 effect on TNBC cell growth depends on the cell-intrinsic-PD-1/PD-L1 pathway independent of adaptive immunity. In addition, we further found that the activation of cell-intrinsic PD-1/PD-L1 pathway in TNBC cells is regulated by the gene expression regulator YB-1. Mechanistically, the results of protein degradation analysis, mRNA translationally active analysis, CLICK chemistry and L-azidohomoalanine (AHA) incorporation assays, immunoprecipitation assay and Dual-Luciferase reporter assay showed that YB-1 promotes PD-1 expression through the translational activation pathway. We provide in vitro and in vivo evidence that silencing YB-1 expression in TNBC cells inhibits cell proliferation, tumorigenesis, and metastasis. However, this inhibition can be rescued by simultaneous exogenous expression of PD-1 and PD-L1 proteins. In conclusion, our results identify TNBC cell-intrinsic functions of the PD-1/PD-L1 axis in tumor growth and metastasis; and revealed PD-1/PD-L1 is a critical effector of YB-1-mediated TNBC proliferation and metastasis in vitro and in vivo.
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