Pathogenesis and Novel Therapeutic Targets of Fatty Liver Disease and Cancer

National Institute On Alcohol Abuse And Alcoholism

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Abstract

Our laboratory has been actively studying the pathogenesis of alcohol-associated liver disease, focusing on characterization of inflammatory cells in alcohol-associated hepatitis and liver cancer. we have identified miR-223, a miRNA that is highly elevated in alcohol-associated liver disease, and plays an important role in regulating tumor environment and liver cancer development. The current treatment for hepatocellular carcinoma (HCC) to block angiogenesis and immunosuppression provides some benefits only for a subset of patients with HCC, thus optimized therapeutic regimens are unmet needs. Addressing these needs require a thorough understanding of the underlying mechanisms by which tumor cells orchestrate an inflamed tumor microenvironment with significant myeloid cell infiltration. MicroRNA-223 (miR-223) is highly expressed in myeloid cells but its role in regulating tumor 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 (CCl4)-treated mice. Genetic deletion of miR-223 markedly exacerbated tumorigenesis 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+CCl4 administration. Bioinformatic analyses of RNA sequencing data revealed a strong correlation between miR-223 levels and tumor 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, it indirectly downregulated them by modulating tumor microenvironment via the suppression of ha ypoxia-inducible factor 1-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 tumor immunosuppression and angiogenesis, which may serve as a novel therapeutic target for HCC.