Pluto Bioinformatics

GSE116374: Inactivation of Irf1 causes susceptibility to colitis-associated colorectal cancer

Bulk RNA sequencing

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. SOURCE: Philippe Gros (philippe.gros@mcgill.ca) - McGill University