Related Experiment Video
Updated: Jan 14, 2026
06:38
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
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Extrachromosomal circular DNA promotes inflammation and hepatocellular carcinoma development
Lap Kwan Chan1,2, Juanjuan Shan1,2,3, Elias Rodriguez-Fos4
1Department of Pathology and Molecular Pathology, University Hospital of Zurich, Zurich, Switzerland.
Science Advances
|October 17, 2025
Summary
Micronuclei in liver cells release extrachromosomal circular DNA (eccDNA), triggering immune responses that drive liver cancer. Blocking the cGAS-STING pathway reduces tumor development in chronic liver disease models.
Area of Science:
- Hepatology
- Cancer Biology
- Immunology
Background:
- Micronuclei and extrachromosomal circular DNA (eccDNA) are observed in chronic liver disease (CLD) and hepatocellular carcinoma (HCC).
- The precise role of micronuclei in HCC development remains unclear.
- Understanding the mechanisms linking liver disease, micronuclei, and cancer is crucial for therapeutic strategies.
Purpose of the Study:
- To investigate the role of micronuclei and eccDNA in promoting HCC development.
- To elucidate the molecular mechanisms by which micronuclei influence hepatic immune responses and carcinogenesis.
- To explore the potential of targeting the cGAS-STING pathway in liver cancer prevention.
Main Methods:
- Development of the nuclei-segregated DNA fiber (NuSeF) assay to analyze DNA replication stress in micronuclei.
- Circular sequencing to quantify eccDNA levels in micronuclei and nuclei.
- Utilizing a CLD mouse model (Mcl1Δhep) and comparing it with other murine liver disease models.
- Genetic deletion of Sting1 in the CLD model to assess the role of the cGAS-STING pathway.
Main Results:
- Increased micronuclei and eccDNA levels were observed in the livers of CLD model mice.
- Micronuclei showed higher susceptibility to replication stress, leading to replication fork slowing.
- Higher eccDNA levels correlated with increased tumor incidence across different liver disease models.
- eccDNA acted as an immunostimulant, promoting hepatocyte-immune cell crosstalk via the cGAS-STING pathway.
- Deletion of Sting1 significantly reduced immune cell chemotaxis and liver tumor incidence.
Conclusions:
- Micronuclei-derived eccDNA triggers hepatic immune responses that promote inflammation-driven liver carcinogenesis in CLD.
- The cGAS-STING pathway is a key mediator of eccDNA-induced liver inflammation and tumor development.
- Targeting eccDNA and the cGAS-STING pathway presents a potential therapeutic strategy for preventing HCC in CLD patients.
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