title: Keratin 8-deletion induced colitis predisposes to murine colorectal cancer enforced by the inflammasome and IL-22 pathway.
abstract: Keratins (K) are intermediate filament proteins important in protection from cellular stress. K8, K18 and K19 are the main components of keratin filaments in colonic epithelia but their role in intestinal diseases remains ambiguous. A function for keratins in intestinal health is supported by the K8-knock-out (K8(-/-)) mouse which manifests an early chronic ulcerative colitis-like inflammatory bowel disease and epithelial hyperproliferation. We tested whether K8(-/-) mice are more susceptible to colorectal cancer (CRC) compared to K8 wild type (K8(+/+)), and K8 heterozygote (K8(+/-)) mice showing increased proliferation but no inflammation. K8(-/-) mice did not develop CRC spontaneously, but had dramatically increased numbers of tumors in the distal colon in the azoxymethane (AOM) and Apc(Min/+) CRC models while neither K8(+/+) nor K8(+/-) mice were susceptible. Upregulation of IL-22 in combination with a complete loss of its negative regulator IL-22BP, and increased downstream STAT3-signaling in K8(-/-) and K8(-/-)Apc(Min/+) colonic epithelia confirmed that the IL-22 pathway, important in inflammation, proliferation and tissue regeneration, was activated. The nearly total loss of IL-22BP correlated with an activated inflammasome leading to increased cleaved caspase-1, and the putative IL-22BP inhibitor, IL-18, as well as a decrease in ALDH1/2. Ablation of K8 in a colorectal cancer cell line similarly resulted in increased IL-18 and decreased ALDH1/2. K8/K18 co-immunoprecipitated with pro-caspase-1, a component of the inflammasome in the colon, which suggests that keratins modulate inflammasome activity and protect the colon from inflammation and tumorigenesis. The K8-null mouse models also provide novel epithelial-derived robust colon-specific CRC models.
authors.affiliation: Biosciences, Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Misiorek
authors.affiliation: Biosciences, Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Iris A K
authors.initials: IAK
authors.lastname: Lähdeniemi
authors.affiliation: Biosciences, Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Nyström
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland.|Department of Physiology, Institute of Biomedicine, University of Turku, Turku 20520, Finland.
authors.forename: Valeriy M
authors.initials: VM
authors.lastname: Paramonov
authors.affiliation: Biosciences, Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.|Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland.|Department of Pathology, University of Turku and Turku University Hospital, Turku 20520, Finland.
authors.forename: Josef A
authors.initials: JA
authors.lastname: Gullmets
authors.affiliation: Biosciences, Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.|Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Saarento
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland.|Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin 20-093, Poland.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Rivero-Müller
authors.affiliation: Department of Food, Water and Cosmetics, Norwegian Institute of Public Health, Oslo 0403, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Husøy
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku 20520, Finland.|MediCity Research Laboratory, University of Turku, Turku, Finland and.
authors.forename: Pekka
authors.initials: P
authors.lastname: Taimen
authors.affiliation: Biosciences, Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku 20520, Finland.|Turku Center for Disease Modeling, University of Turku, Turku 20520, Finland.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Toivola
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D003092:Colitis / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics; D053533:Keratin-8 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D050697:Retinal Dehydrogenase / Q000235:genetics; D017384:Sequence Deletion; D000097043:Interleukin-22
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D058847:Inflammasomes; D007378:Interleukins; D007527:Isoenzymes; D053533:Keratin-8; D050697:Retinal Dehydrogenase; D000097043:Interleukin-22; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse