Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Gut. 2023 Oct;72(10):1942-1958. doi: 10.1136/gutjnl-2022-327924. Epub 2023 Jan 2.
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.
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)-treated mice.
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 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.
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.
目前针对肝细胞癌（HCC）的治疗方法是阻断血管生成和免疫抑制，但仅对一部分 HCC 患者有效，因此需要优化治疗方案，这需要深入了解肿瘤细胞协调富含髓样细胞浸润的炎症肿瘤微环境的潜在机制。微小 RNA-223（miR-223）在髓样细胞中高度表达，但它在调节肿瘤微环境中的作用尚不清楚。
野生型和 miR-223 敲除小鼠分别接受二乙基亚硝胺（DEN）注射或慢性四氯化碳（CCl）处理的原位 HCC 细胞植入引起的两种炎症相关 HCC 小鼠模型。
miR-223 的遗传缺失显著加剧了炎症相关 HCC 的肿瘤发生。与野生型小鼠相比，DEN+CCl 给药后 miR-223 敲除小鼠有更多浸润的程序性死亡 1（PD-1）T 细胞和程序性死亡配体 1（PD-L1）巨噬细胞。RNA 测序数据的生物信息学分析显示，miR-223 水平与肿瘤缺氧之间存在很强的相关性，肿瘤缺氧是调节 PD-1/PD-L1 的已知条件。体内和体外机制研究表明，miR-223 不是直接针对免疫细胞中的 PD-1 和 PD-L1，而是通过抑制 HCC 中缺氧诱导因子 1α驱动的 CD39/CD73-腺苷途径来间接下调它们，从而调节肿瘤微环境。此外，通过腺病毒递送 miR-223 基因抑制了两种 HCC 模型中的血管生成和缺氧介导的 PD-1/PD-L1 激活，从而阻碍了 HCC 的进展。
miR-223 在调节缺氧诱导的肿瘤免疫抑制和血管生成中起着关键作用，可能成为 HCC 的新治疗靶点。
