Abstract
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.
Highlights
Population studies have demonstrated that in humans, IBD is under complex genetic control with >225 risk loci mapped in large cohort association studies (GWAS)[6,7,8]
We conducted a second experiment in which B6 and Irf1−/− mutants received AOM and only two 2% dextran sodium sulfate (DSS) treatments, with mice sacrificed at the end of week 8
Interferon regulatory factor 1 (IRF1) plays a critical role in the ontogeny and function of the myeloid and lymphoid compartments of the immune system, in activation of intrinsic anti-microbial defenses and production of inflammatory cytokines activating early immune response by myeloid cells, resulting in primary defects in myeloid and lymphoid cell maturation and secondary defects in activation of T cell-specific immune responses upon its loss[40,41,42,43]
Summary
Population studies have demonstrated that in humans, IBD is under complex genetic control with >225 risk loci mapped in large cohort association studies (GWAS)[6,7,8]. Irf1−/− mice show active colitis in response to the irritant dextran sodium sulfate (DSS)[16,17], and human IRF1 mRNA is increased in lamina propria mononuclear cells from CD patients[18], suggesting that IRF1 may contribute to inflammation in IBD, and possibly to progression to CA-CRC. Analysis of The Cancer Genome Atlas (TCGA) database for IRF1 expression in human colorectal cancer patients revealed a statistically significant reduction of IRF1 in colorectal cancer patient tumors of Stage 1, 3, and 4 Together, these results suggest a critical role for IRF1 in regulating the type and intensity of inflammatory response in the colon, contributing to establishment of permissive conditions for progression of IBD to CA-CRC
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