PD-L1 Under Regulation of miR-429 Influences the Sensitivity of Gastric Cancer Cells to TRAIL by Binding of EGFR
PD-L1 Under Regulation of miR-429 Influences the Sensitivity of Gastric Cancer Cells to TRAIL by Binding of EGFR
复制标题
miR-429调控的PD-L1通过结合EGFR影响胃癌细胞对TRAIL的敏感性
DOI：
10.3389/fonc.2020.01067
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发表时间：
2020-07-22
影响因子：
4.7
通讯作者：
Xu, Ling
中科院分区：
文献类型：
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作者：
Lv, Jinqi;Guo, Tianshu;Xu, Ling
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）作为一种肿瘤治疗药物受到了广泛的关注，这是由于其具有高度的肿瘤靶向性，对健康组织的毒性最小。胃癌（GCa）细胞显示高水平的TRAIL抗性。表皮生长因子受体（EGFR）拮抗TRAIL诱导的细胞凋亡，但这些作用的机制尚不清楚。我们过去的研究证实了TRAIL耐药细胞（BGC 823和SGC 7901）和TRAIL敏感细胞（HGC 27和MKN 45）。使用microRNA阵列筛选与TRAIL敏感性相关的miR-429。模拟物和抑制剂的转染证实miR-429与GCa TRAIL抗性呈负相关。通过基因沉默和恢复实验，确定miR-429的靶基因为PD-L1，PD-L1与TRAIL耐药正相关。使用免疫共沉淀（co-IP）和邻位连接试验，我们证明PD-L1的促生存作用是通过EGFR的结合和激活介导的。细胞活力实验表明，PD-L1是维持TRAIL处理的细胞中细胞活力的关键。这表明PD-L1通过miR-429调节结合并参与EGFR活化，以拮抗TRAIL诱导的细胞凋亡。这为EGFR单克隆抗体包括西妥昔单抗、PD-L1抑制剂和人重组TRAIL联合治疗胃癌提供了新的理论依据，并可筛选目前对TRAIL治疗敏感的患者。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received extensive attention as a cancer therapeutic due to its high propensity for tumor targeting with minimal toxicity to healthy tissue. Gastric cancer (GCa) cells show high levels of TRAIL resistance. Epidermal growth factor receptor (EGFR) antagonizes TRAIL-induced apoptosis, but the mechanisms of these effects remain unclear. Our past research confirmed TRAIL-resistant (BGC823 and SGC7901) and TRAIL-sensitive cells (HGC27 and MKN45). miR-429 associated with TRAIL sensitivity was screened using microRNA arrays. The transfection of mimics and inhibitors confirmed that miR-429 negatively correlated with GCa TRAIL resistance. The target gene of miR-429 was identified as PD-L1, which positively correlated with TRAIL resistance through gene silencing and recovery experiments. Using co-immunoprecipitation (co-IP) and proximity ligation assay, we demonstrated that the pro-survival effects of PD-L1 are mediated through the binding and activation of EGFR. Cell viability experiments demonstrated that PD-L1 is key to the maintenance of cell viability in TRAIL-treated cells. This indicated that PD-L1 binds to and participates in EGFR activation through miR-429 regulation to antagonize TRAIL-induced apoptosis. This provides a new theoretical basis for the combination of the EGFR monoclonal antibodies including cetuximab, PD-L1 inhibitors, and human recombinant TRAIL in gastric cancer therapy and can filter patients who are currently sensitive to TRAIL treatment.