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Negative feedback regulation of IFN-gamma pathway by IFN regulatory factor 2 in esophageal cancers

Yan Wang1, Dongping Liu, Pingping Chen

  • 1Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Cancer Research
|February 19, 2008
PubMed

Insights

Interferon-gamma (IFN-gamma) normally fights cancer but can promote esophageal cancer growth. This occurs when IFN-gamma increases Interferon regulatory factor 2 (IRF-2), which then reduces IFN-gamma receptors, making cancer cells resistant to IFN-gamma therapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Interferon-gamma (IFN-gamma) is an antitumor cytokine that inhibits cell proliferation and induces apoptosis.
  • Interferon regulatory factor 2 (IRF-2) can block IFN-gamma effects by repressing IFN-gamma-induced gene transcription.
  • The role of IFN-gamma in human esophageal cancer cells remains underexplored.

Purpose of the Study:

  • To investigate the functions of IFN-gamma in human esophageal cancer cells.
  • To elucidate the mechanism by which IFN-gamma influences esophageal cancer progression.
  • To explore the relationship between IFN-gamma, IRF-2, and IFN-gamma receptors (IFNGR) in esophageal cancer.

Main Methods:

  • Analysis of clinical esophageal cancer samples to assess levels of IFN-gamma, IRF-2, and IFNGR1.
  • In vitro experiments using human esophageal cancer cells to study the effects of IFN-gamma and IRF-2.
  • Investigation of IRF-2 binding to the IFNGR1 promoter using molecular techniques.

Main Results:

  • IFN-gamma levels were increased in tumor tissues and correlated with tumor progression and IRF-2 expression.
  • IFNGR1 levels were decreased in tumor tissues and negatively correlated with tumor progression and IRF-2 expression.
  • Low concentrations of IFN-gamma induced IRF-2 expression, promoting cell growth and suppressing IFNGR1 transcription, thereby reducing cancer cell sensitivity to IFN-gamma.

Conclusions:

  • A novel IRF-2-mediated inhibitory mechanism for the IFN-gamma pathway in esophageal cancer was identified.
  • IFN-gamma up-regulates IRF-2, which in turn down-regulates IFNGR1, leading to enhanced resistance to IFN-gamma.
  • IRF-2 may act as a mediator for IFN-gamma and IFNGR1 functions in human esophageal cancers, suggesting potential therapeutic targeting.

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