GSE116374
Inactivation of Irf1 causes susceptibility to colitis-associated colorectal cancer
The incidence of colorectal cancer (CRC) is increased in patients afflicted by inflammatory bowel diseases (IBD) The cellular and molecular mechanisms that link chronic inflammation of the gut and increased CRC susceptibility are poorly understood. Risk of IBD is strongly influenced by genetic factors, including the IBD5 locus (5q31), harboring the IRF1 gene. A cause to effect relationship between chronic inflammation and CRC, and a possible role of IRF1 were studied in Irf1-/- mutant mice in a model of colitis associated CRC (CA-CRC) induced by azoxymethane and the irritant 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, enhanced crypt cells proliferation and reduced tissue repair in Irf1-/- mutants, and this prior to appearance of tumors. A considerable infiltration of leukocytes is seen at this early stage in Irf1-/- colons, this infiltrate being composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells, mast cells, and CD3+ lymphoid cells. Studies in bone marrow chimeras show that differential susceptibility to CA-CRC of Irf1-/- vs. B6 controls is fully transferable by hematopoietic cells. Studies in human datasets confirm that transcripts signatures seen in Irf1-/- mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with CRC. In addition, IRF1 expression in the colon is significantly decreased in late stage CRC (stages 3, 4) associated with poorer prognosis. These studies suggest that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ in gut establishing microbial-driven chronic inflammation and possibly creating a tumor promoting environment. Overall design: We had found that interferon regulatory factor 1 (Irf1) knockout mice developed significantly higher colorectal tumor burden upon AOM/DSS treatments compared to resistant control B6 mice. Based on these results, we decided to investigate the molecular mechanisms by which these genes contribute to CA-CRC through transcriptome profiling. RNA sequencing was done on the colons of B6 and Irf1-/- untreated mice and mice at day 26 after one AOM and one DSS treatment (mice received one injection 7mg/kg of AOM (d1) followed by one 4-day cycle of DSS (2%; d8-d11) and were sacrificed at d26). The D26 timepoint was selected to elucidate how the biological systems in the colon were altered in our CA-CRC susceptible mice prior to the establishment of tumorigenesis. Colons of untreated and 26 days post-AOM/DSS treated B6 WT and Irf1 KO mice were examined by transcriptional profiling using three biological replicates per group.