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An infectious murine model for hepacivirus-associated fibrosis and hepatocellular carcinoma

ABSTRACT: The NrHV-HCC model represents the first immunocompetent infectious system that faithfully recapitulates the multistage progression from chronic viral hepatitis to spontaneous hepatocellular carcinoma, bridging a long-standing translational gap between mechanistic mouse studies and human liver cancer. By mirroring the immunopathological, molecular, and sex-associated features of chronic HCV infection, this model provides an unparalleled platform to investigate virus-host interactions underlying fibrosis and oncogenesis. High HCC penetrance and the genetically tractable C57BL/6 background further enhance experimental utility, enabling precise mechanistic dissection and genetic manipulation in a physiologically relevant setting. The capacity to study spontaneous tumor development in the context of natural infection allows for rigorous testing of antifibrotic and anti-cancer strategies, while the persistence of oncogenic potential after viral clearance raises important questions about irreversible disease reprogramming and elevated cancer risk following viral cure - issues of direct relevance to patients cured of HCV.

ORGANISM(S): Mus musculus

PROVIDER: GSE265927 | GEO | 2026/03/15

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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An infectious murine model for hepacivirus-associated fibrosis and hepatocellular carcinoma

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