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Updated: Mar 20, 2026

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer

Yuji Eso1, Atsushi Takai1, Tomonori Matsumoto1

  • 1Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Cancer Research
|June 5, 2016
PubMed

Insights

Chronic inflammation promotes cancer by increasing genetic instability. This study reveals that inflammation-induced downregulation of DNA mismatch repair gene MSH2 contributes to liver cancer development by causing mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Inflammation is a known risk factor for cancer development.
  • The mechanisms linking chronic inflammation to increased genetic instability are not fully understood.

Purpose of the Study:

  • To investigate the role of inflammation-mediated MSH2 dysregulation in hepatocarcinogenesis.
  • To elucidate the molecular pathways involved in inflammation-induced genetic instability.

Main Methods:

  • Utilized mouse models with MSH2 deficiency and/or AICDA expression in hepatocytes.
  • Analyzed transcriptional changes and mutation signatures in liver tumors.
  • Investigated the role of TNFα, NF-κB, and miR-21 in MSH2 regulation.

Main Results:

  • TNFα stimulation downregulated MSH2 via NF-κB-dependent miR-21 expression in hepatocytes.
  • Liver cancers developed in mice with MSH2 deficiency and/or AICDA expression.
  • Mutation signatures in mouse models closely mimicked human hepatocellular carcinoma.

Conclusions:

  • Inflammation-mediated downregulation of MSH2 is a potential mechanism driving genetic alterations in liver cancer.
  • Dysregulation of DNA mismatch repair contributes to inflammation-associated tumorigenesis.

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