Extrachromosomal circular DNA promotes inflammation and hepatocellular carcinoma development

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Abstract Two decades after the initial report on increased micronuclei in human chronic liver disease (CLD) and hepatocellular carcinoma (HCC), their role in HCC development is still poorly understood. Here we show that micronuclei in hepatocytes trigger hepatic immune response and promote HCC development via an increased level of extrachromosomal circular DNA (eccDNA). Livers from a CLD model ( Mcl1 Δhep mice) show increased micronuclei in parallel to eccDNA. Circular sequencing confirms higher eccDNA levels in micronuclei compared to primary nuclei. We developed nuclei-segregated DNA fiber (NuSeF) assay to show that micronuclei are more susceptible to replication stress, showing increased replication fork slowing. By comparing different murine liver disease models, high eccDNA is correlated with increased tumor incidence. EccDNA is a strong immunostimulant and promotes a crosstalk between hepatocytes and immune cells through the cGAS-STING pathway. Deletion of Sting1 in Mcl1 Δhep mice reduces immune cell chemotaxis, as well as tumor incidence. Our findings suggest that eccDNA from micronuclei mediates inflammation-driven liver carcinogenesis in CLD.

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