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Oncogenic Ki-ras inhibits the expression of interferon-responsive genes through inhibition of STAT1 and STAT2

Lidija Klampfer1, Jie Huang, Georgia Corner

  • 1Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, 111 E. 210th Street, Bronx, NY 10467, USA. lklampf@aecom.yu.edu

The Journal of Biological Chemistry
|September 16, 2003
PubMed

Insights

Activating Ki-ras mutations in cancer can block interferon signaling by inhibiting STAT1 and STAT2. This makes tumors insensitive to interferon gamma, potentially allowing them to evade immune surveillance.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Endogenous interferon gamma (IFNγ) is crucial for anti-tumor immunity.
  • Tumors resistant to IFNγ exhibit increased tumorigenicity and immune evasion.
  • Oncogenic mutations, like those in Ki-ras, are common in various cancers.

Purpose of the Study:

  • To investigate the mechanism by which activating Ki-ras mutations affect IFNγ signaling.
  • To determine if Ki-ras mutations contribute to tumor insensitivity to interferons.
  • To explore the impact of Ki-ras on the expression of key IFN signaling components.

Main Methods:

  • Analysis of STAT1 and STAT2 expression in colon cancer cell lines with and without Ki-ras mutations.
  • Comparison of IFN-responsive gene expression in wild-type versus mutant Ki-ras cell lines.
  • Inactivation of mutant Ki-ras allele in HCT116 cells and assessment of STAT1, STAT2, and IRF-9 restoration.
  • Reporter gene assays to evaluate IFNγ-stimulated transcription in the presence of RasV12.
  • Endogenous expression analysis of STAT1 and STAT2 in 293T cells expressing RasV12.

Main Results:

  • Activating Ki-ras mutations were found to inhibit the expression of STAT1 and STAT2.
  • Colon cancer cell lines with Ki-ras mutations showed reduced expression of IFN-responsive genes.
  • Inactivation of mutant Ki-ras in HCT116 cells restored STAT1, STAT2, and IRF-9 expression.
  • RasV12 expression impaired IFNγ-stimulated transcription of a STAT1-dependent reporter gene.
  • Oncogenic RasV12 expression inhibited endogenous STAT1 and STAT2 expression in 293T cells.

Conclusions:

  • Signaling from activated Ki-ras interferes with the IFN/STAT pathway.
  • This interference modulates cancer cell responsiveness to interferons.
  • Tumors with activating Ki-ras mutations may evade immune surveillance due to reduced IFNγ responsiveness.

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