MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression

免疫抑制 癌症研究 肝细胞癌 肿瘤微环境 血管生成 髓样 缺氧(环境) 小RNA 医学 生物 免疫学 化学 肿瘤细胞 氧气 有机化学 基因 生物化学
作者
Yaojie Fu,Bryan Mackowiak,Dechun Feng,Hongkun Lu,Yukun Guan,Taylor Lehner,Hongna Pan,Xin Wei Wang,Yong He,Bin Gao
出处
期刊:Gut [BMJ]
卷期号:72 (10): 1942-1958 被引量:66
标识
DOI:10.1136/gutjnl-2022-327924
摘要

Objective The current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimised therapeutic regimens are unmet needs, which require a thorough understanding of the underlying mechanisms by which tumour cells orchestrate an inflamed tumour microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumour microenvironment remains unknown. Design Wild-type and miR-223 knockout mice were subjected to two mouse models of inflammation-associated HCC induced by injection of diethylnitrosamine (DEN) or orthotopic HCC cell implantation in chronic carbon tetrachloride (CCl 4 )-treated mice. Results Genetic deletion of miR-223 markedly exacerbated tumourigenesis in inflammation-associated HCC. Compared with wild-type mice, miR-223 knockout mice had more infiltrated programmed cell death 1 (PD-1 + ) T cells and programmed cell death ligand 1 (PD-L1 + ) macrophages after DEN+CCl 4 administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumour hypoxia, a condition that is well-documented to regulate PD-1/PD-L1. In vivo and in vitro mechanistic studies demonstrated that miR-223 did not directly target PD-1 and PD-L1 in immune cells rather than indirectly downregulated them by modulating tumour microenvironment via the suppression of hypoxia-inducible factor 1α-driven CD39/CD73-adenosine pathway in HCC. Moreover, gene delivery of miR-223 via adenovirus inhibited angiogenesis and hypoxia-mediated PD-1/PD-L1 activation in both HCC models, thereby hindering HCC progression. Conclusion The miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.
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