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

Abstract

ObjectiveThe 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.DesignWild-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 (CCl4)-treated mice.ResultsGenetic 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+CCl4administration. 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.ConclusionThe miR-223 plays a critical role in modulating hypoxia-induced tumour immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.

Investigation of the Proteasome 26S Subunit, ATPase Family Genes as Potential Prognostic Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma

“…Recently, studies in HCC have found that myeloid cells (mainly the monocyte-derived macrophages) expressed PD-L1 play a critical role in regulating the hypoxic tumor microenvironment and immune escape of HCC. 45,46 According to our results, we speculate that through this mechanism PSMCs may be involved in the regulation of the immune response in HCC. CTLA4 inhibition can lead to increased activation of naive CD4 and CD8 T cells by acting on T cell-antigen-presenting cell immune synapse.…”

Lenvatinib Induces Immunogenic Cell Death and Triggers Toll-Like Receptor-3/4 Ligands in Hepatocellular Carcinoma

“…In this study, we mainly focus on the regulation of TLR on PD-L1 expression in tumor cells, but tumor-associated macrophage also plays a critical role in the development of HCC. 31 , 32 …”

“…focus on the regulation of TLR on PD-L1 expression in tumor cells, but tumor-associated macrophage also plays a critical role in the development of HCC. 31,32 ICD-associated DAMPs activate antitumor immune responses by activating the innate immunity represented by TLR3 and TLR4. 33,34 Interestingly, the expressions of TLR3 and TLR4 increased in lenvatinib-treated cells and played contrasting roles in tumors.…”

Noncoding RNAs in Hepatocellular Carcinoma: Potential Applications in Combined Therapeutic Strategies and Promising Candidates of Treatment Response

“…The authors proposed an intriguing model for chronic inflammation-associated HCCs in which myeloid cells represent the source for miR-223 transfer to cancer cells, where miR-223 inhibits HIF-1A expression and indirectly influences the composition of the TME by suppressing the HIF-1A-driven CD39/CD73-adenosine pathway that contributes to PD-1 and PD-L1 upregulation in immune cells. Adenovirus-mediated gene delivery of miR-223 in two inflammatory-associated models of HCC hindered tumor development and progression by inhibiting angiogenesis and hypoxia-mediated PD1/PD-L1 activation in T cells and macrophages, proving the therapeutic potential of miR-223 in blocking the immunosuppressive tumor microenvironment in HCC [109]. Notably, "RNA-RNA" crosstalk relies not only on noncoding RNAs functioning as "microRNA sponges" but also on coding mRNAs, which can relieve the inhibitory effect of miRNAs on their target genes by ceRNA activity.…”