Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer.
Thiviya JeyakumarNassima FodilLauren Van Der KraakCharles MeunierRomain CayrolKevin McGregorDavid LanglaisCelia M T GreenwoodNicole BeaucheminPhilippe GrosPublished in: Scientific reports (2019)
The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1-/- mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1-/- mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1-/- colons at this early stage, and is composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells and other granulocytes, as well as CD4+ lymphoid cells. Differential susceptibility to CA-CRC of Irf1-/- vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1-/- mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.
Keyphrases
- dendritic cells
- rna seq
- induced apoptosis
- early onset
- oxidative stress
- bone marrow
- early stage
- single cell
- poor prognosis
- genome wide
- ulcerative colitis
- signaling pathway
- type diabetes
- gene expression
- endothelial cells
- squamous cell carcinoma
- cell proliferation
- acute myeloid leukemia
- radiation therapy
- late onset
- long non coding rna
- lymph node
- mesenchymal stem cells
- drug induced
- high fat diet induced
- quantum dots
- dna methylation
- sentinel lymph node
- fine needle aspiration