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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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Constitutive Notch2 signaling induces hepatic tumors in mice

Michael T Dill1, Luigi Tornillo, Thorsten Fritzius

  • 1Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.

Hepatology (Baltimore, Md.)
|November 24, 2012
PubMed
Abstract

Insights

Constitutive Notch2 signaling promotes liver cancer. This study shows that activating Notch2 in mice leads to hepatocellular carcinoma and cholangiocarcinoma, accelerating tumor growth and dedifferentiation.

Area of Science:

  • Hepatology
  • Oncology
  • Molecular Biology

Background:

  • Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCC) are leading causes of cancer death.
  • Notch2 signaling is crucial for liver development and differentiation.
  • The role of Notch2 in liver carcinogenesis remains unclear.

Purpose of the Study:

  • To investigate the oncogenic potential of constitutive Notch2 signaling in liver cancer.
  • To determine if Notch2 regulates proliferation and differentiation in liver carcinogenesis.

Main Methods:

  • Liver-specific expression of Notch2 intracellular domain (N2ICD) in mice.
  • Utilized the diethylnitrosamine (DEN) HCC carcinogenesis model.
  • Analyzed gene expression (Sox9, Albumin, Alpha-fetoprotein, HNF4α) and cell proliferation.

Main Results:

  • Constitutive N2ICD expression induced HCC and biliary hyperplasia in mice.
  • N2ICD signaling upregulated pro-proliferative genes and increased hepatocyte and biliary epithelial cell proliferation.
  • Notch2 signaling accelerated DEN-induced HCC formation, leading to larger, less differentiated tumors.
  • DEN(N2ICD) mice developed CCC, associated with HNF4α re-expression.

Conclusions:

  • Constitutive Notch2 signaling plays an oncogenic role in liver cancer development.
  • Notch2 activation promotes proliferation and dedifferentiation in liver carcinogenesis.
  • Aberrant Notch2 signaling contributes to both HCC and CCC formation.

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