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Loss of colonic primary cilia promotes inflammation and carcinogenesis

ABSTRACT: Primary cilia (PC) are important signaling hubs in cells and we explored their role in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts and exposure of mice to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced acute colitis decreased PC numbers. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Secretome and immunohistochemical analyses of DSS-treated mice displayed an elevated production of the pro-inflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminished PC presence in primary fibroblast cultures. This was triggered by IL-6 as identified by RNAseq analysis together with blocking experiments, suggesting an activation loop between IL-6 production and PC loss. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.

INSTRUMENT(S): maXis

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Colon

SUBMITTER: Maria Concetta Cufaro

LAB HEAD: Damiana Pieragostino

PROVIDER: PXD033440 | Pride | 2022-11-29

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	KO_colon_distale_01_new_C4_01_12222.d.zip	Other
	KO_colon_distale_02_new_C4_01_12226.d.zip	Other
	KO_colon_distale_03_new_C4_01_12230.d.zip	Other
	KO_colon_distale_04_new_C4_01_12262.d.zip	Other
	WT_colon_distale_01_new_C2_01_12210.d.zip	Other

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Loss of colonic primary cilia promotes inflammation and carcinogenesis

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