Extrachromosomal circular DNA promotes inflammation and hepatocellular carcinoma development
Preprint
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.Keywords
All Related Versions
- Published version: Science Advances, 11 (42), eadw0272.
This publication has 43 references indexed in Scilit:
- Block of NF-kB signaling accelerates MYC-driven hepatocellular carcinogenesis and modifies the tumor phenotype towards combined hepatocellular cholangiocarcinomaCancer Letters, 2019
- The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell DeathCell, 2019
- A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer DevelopmentCancer Cell, 2017
- Production of Extrachromosomal MicroDNAs Is Linked to Mismatch Repair Pathways and Transcriptional ActivityCell Reports, 2015
- Metabolic Activation of Intrahepatic CD8+ T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with HepatocytesCancer Cell, 2014
- ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC DevelopmentCancer Cell, 2014
- Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer DevelopmentCell, 2011
- Mcl‐1; the molecular regulation of protein functionFEBS Letters, 2010
- Hepatocyte‐specific deletion of the antiapoptotic protein myeloid cell leukemia‐1 triggers proliferation and hepatocarcinogenesis in mice†Hepatology, 2010
- Detection of micronuclei formation and nuclear anomalies in regenerative nodules of human cirrhotic livers and relationship to hepatocellular carcinomaCancer Genetics and Cytogenetics, 2004