Hypoxia-associated circPRDM4 promotes immune escape via HIF-1α regulation of PD-L1 in hepatocellular carcinoma

作者：Zhiqiang Chen, Xueliang Zuo, Juan Cai, Yao Zhang, Guoyong Han, Long Zhang, Wenzhou Ding, Jindao Wu, Xuehao Wang · 发表于：Experimental Hematology and Oncology · 年份：2023 · DOI：10.1186/s40164-023-00378-2 · 被引用次数：85 · 研究领域：Circular RNAs in diseases、Inflammasome and immune disorders、Ferroptosis and cancer prognosis

Abstract Background Hypoxia is a hallmark of cancer, and is closely intertwined with tumor immune evasion. Circular RNAs (circRNAs) have been implicated in tumor response to immune checkpoint blockades. However, hypoxia-associated circRNAs that orchestrate the association between hypoxia and response to immunotherapy remain poorly understood. Here, we aimed to determine the roles of hypoxia-associated circRNAs in immune escape of hepatocellular carcinoma (HCC) cells. Methods Differentially expressed hypoxia-associated circRNAs were determined using high-throughput sequencing technology. HCC patients treated with PD-1 blockade were enrolled to assess the clinical significance of circPRDM4. RT-qPCR, western blotting, flow cytometry, T cell-mediated tumor cell killing assay, and enzyme linked immunosorbent assay were used to investigate the roles of circPRDM4 in immune escape of HCC cells in vitro. Patient-derived xenograft mouse models and adoptive human tumor infiltrating lymphocyte-CD8 + T cell transfer were adopted to evaluate the effects of circPRDM4 in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, chromatin immunoprecipitation, chromatin isolation by RNA purification, dual-luciferase reporter assays, dot blotting, DNA in situ hybridization, and immunoprecipitation were utilized to examine the interaction between circPRDM4, HIF-1α, and CD274 promoter. Results We identified circPRDM4 as a hypoxia-associated circRNA in HCC. circPRDM4 was upregulated in resp...