PD-L1 敲低通过调节 ZEB1 触发的 EMT 抑制非小细胞肺癌的血管生成拟态。

PD-L1 knockdown suppresses vasculogenic mimicry of non-small cell lung cancer by modulating ZEB1-triggered EMT.

机构信息

Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Molecular Diagnosis Center, First Affiliated Hospital, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China.

Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People's Republic of China.

出版信息

BMC Cancer. 2024 May 23;24(1):633. doi: 10.1186/s12885-024-12390-8.

DOI:10.1186/s12885-024-12390-8

PMID:38783271

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11118770/

Abstract

BACKGROUND

PD-L1 overexpression is commonly observed in various malignancies and is strongly correlated with poor prognoses for cancer patients. Moreover, PD-L1 has been shown to play a significant role in promoting angiogenesis and epithelial-mesenchymal transition (EMT) processes across different cancer types.

METHODS

The relationship between PD-L1 and vasculogenic mimicry as well as epithelial-mesenchymal transition (EMT) was explored by bioinformatics approach and immunohistochemistry. The functions of PD-L1 in regulating the expression of ZEB1 and the EMT process were assessed by Western blotting and q-PCR assays. The impact of PD-L1 on the migratory and proliferative capabilities of A549 and H1299 cells was evaluated through wound healing, cell invasion, and CCK8 assays following siRNA-mediated PD-L1 knockdown. Tube formation assay was utilized to evaluate the presence of VM structures.

RESULTS

In this study, increased PD-L1 expression was observed in A549 and H1299 cells compared to normal lung epithelial cells. Immunohistochemical analysis revealed a higher prevalence of VM structures in the PD-L1-positive group compared to the PD-L1-negative group. Additionally, high PD-L1 expression was also found to be significantly associated with advanced TNM stage and increased metastasis. Following PD-L1 knockdown, NSCLC cells exhibited a notable reduction in their ability to form tube-like structures. Moreover, the levels of key EMT and VM-related markers, including N-cadherin, MMP9, VE-cadherin, and VEGFA, were significantly decreased, while E-cadherin expression was upregulated. In addition, the migration and proliferation capacities of both cell lines were significantly inhibited after PD-L1 or ZEB1 knockdown.

CONCLUSIONS

Knockdown PD-L1 can inhibit ZEB1-mediated EMT, thereby hindering the formation of VM in NSCLC.

摘要

背景

PD-L1 过表达在各种恶性肿瘤中很常见，与癌症患者的预后不良密切相关。此外，PD-L1 已被证明在促进不同癌症类型的血管生成和上皮-间充质转化（EMT）过程中发挥重要作用。

方法

通过生物信息学方法和免疫组织化学方法探讨了 PD-L1 与血管生成拟态和上皮-间充质转化（EMT）之间的关系。通过 Western blot 和 q-PCR 检测评估 PD-L1 调节 ZEB1 表达和 EMT 过程的功能。通过 siRNA 介导的 PD-L1 敲低后，通过划痕愈合、细胞侵袭和 CCK8 测定评估 PD-L1 对 A549 和 H1299 细胞迁移和增殖能力的影响。通过管形成测定评估 VM 结构的存在。

结果

在这项研究中，与正常肺上皮细胞相比，A549 和 H1299 细胞中 PD-L1 的表达增加。免疫组织化学分析显示，PD-L1 阳性组中 VM 结构的发生率高于 PD-L1 阴性组。此外，高 PD-L1 表达也与晚期 TNM 分期和转移增加显著相关。PD-L1 敲低后，非小细胞肺癌细胞形成管状结构的能力显著降低。此外，关键 EMT 和 VM 相关标志物，包括 N-钙黏蛋白、MMP9、VE-钙黏蛋白和 VEGFA 的水平显著降低，而 E-钙黏蛋白表达上调。此外，PD-L1 或 ZEB1 敲低后，两种细胞系的迁移和增殖能力均受到显著抑制。