Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer

Area of Science:

• Immunology
• Gastroenterology
• Oncology

Background:

• Mechanisms linking chronic gut inflammation (IBD) and colorectal cancer (CRC) are unclear.
• The IBD5 locus, containing the IRF1 gene, is linked to IBD risk.
• The role of IRF1 in CRC development during chronic inflammation requires investigation.

Purpose of the Study:

• To investigate the cause-to-effect relationship between chronic inflammation and CRC.
• To determine the role of IRF1 in colitis-associated colorectal cancer (CA-CRC).

Main Methods:

• Utilized Irf1 knockout (Irf1-/-) mice in an azoxymethane/dextran sulfate sodium (AOM/DSS) induced CA-CRC model.
• Performed transcript profiling (RNA-seq) and immunostaining on mouse colons.
• Conducted bone marrow chimera studies to assess hematopoietic cell contribution.
• Analyzed clinical specimens from IBD and CRC patients.

Main Results:

• Irf1-/- mice exhibited hyper-susceptibility to CA-CRC with early onset, increased tumor burden, and rapid lethality.
• Loss of Irf1 led to heightened colonic inflammation, enhanced enterocyte proliferation, and significant infiltration of proinflammatory myeloid cells and CD4+ T cells prior to tumor development.
• Susceptibility to CA-CRC was transferable via hematopoietic cells.
• Transcript signatures from Irf1-/- mice mirrored those in human IBD and CRC specimens.
• Decreased IRF1 expression in human colon cancer (stages 3-4) correlated with poorer prognosis.

Conclusions:

• Loss of IRF1 promotes CA-CRC development by altering immune cell populations and creating a pro-tumorigenic environment during chronic inflammation.
• IRF1 plays a critical role in regulating the immune response within the gut during inflammation, impacting cancer susceptibility.
• IRF1 status may serve as a prognostic marker in colorectal cancer.