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MicroRNA-146a protects against Hepatocellular Carcinoma through suppression of CCL5

ABSTRACT: The microRNA miR-146a regulates several aspects of chronic inflammation, including the Hepatocellular Carcinoma (HCC) risk factor hepatosteatosis. Here, we find that loss of miR-146a leads to significantly increased tumor burden in a mouse model of HCC. Notably, this miR-146a-/- phenotype is most pronounced in females, who are typically not sensitive to this model. Mechanistically, we identified increases in dysfunctional CD8+ T-cells that express high levels of CCL5 and resemble Taa cells, as well as elevated levels of myeloid cells that resemble monocytic myeloid-derived suppressor cells (M-MDSCs), a class of myeloid cells that suppress tumor immunity. Deletion of Ccl5 from miR-146a-deficient mice returned tumor growth and the aberrant myeloid cell population to wild-type (WT) levels. Surprisingly, deletion of Ccl5 did not rescue the gross metabolic phenotype observed in miR-146a-/- mice subjected to HCC induction, indicating independent roles for miR-146a in its regulation of HCC and metabolic disease. Taken together, this work reveals a critical host protective role for miR-146a in HCC through suppression of CCL5, providing an impetus for targeting these pathways as a means to combat HCC. Further, the correlations with disease and Taa cells suggest that aging may increase HCC risk through the accumulation of Taa cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE300674 | GEO | 2026/01/05

REPOSITORIES: GEO

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Project description:Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in cellular homeostasis within the liver and deregulation of the miRNome has been associated with liver disease including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross-talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here, we combined a hepatocyte-like based model system, high-throughput small RNA-sequencing, computational analysis and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least two-fold including miRNAs that were previously described to target genes associated with inflammation, fibrosis and cancer development. Further investigation demonstrated that miR-146a-5p was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes as well as in liver tissues from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p over-expression is related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p positively impacts on late steps of the viral replication cycle thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. To explore the functional relevance of miR-146a-5p up-regulation, we performed a genome-wide transcriptomic analysis of hepatocyte-like cells upon ectopic miR-146a-5p expression.

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MicroRNA-146a protects against Hepatocellular Carcinoma through suppression of CCL5

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