Targeted deletion of keratin 8 in intestinal epithelial cells disrupts tissue integrity and predisposes to tumorigenesis in the colon View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-12-24

AUTHORS

Carl-Gustaf A. Stenvall, Mina Tayyab, Tove J. Grönroos, Maria A. Ilomäki, Keijo Viiri, Karen M. Ridge, Lauri Polari, Diana M. Toivola

ABSTRACT

Keratin 8 (K8) is the main intestinal epithelial intermediate filament protein with proposed roles for colonic epithelial cell integrity. Here, we used mice lacking K8 in intestinal epithelial cells (floxed K8 and Villin-Cre1000 and Villin-CreERt2) to investigate the cell-specific roles of intestinal epithelial K8 for colonocyte function and pathologies. Intestinal epithelial K8 deletion decreased K8 partner proteins, K18–K20, 75–95%, and the remaining keratin filaments were located at the colonocyte apical regions with type II K7, which decreased 30%. 2-Deoxy-2-[18F]-fluoroglucose positron emission tomography in vivo imaging identified a metabolic phenotype in the lower gut of the conditional K8 knockouts. These mice developed intestinal barrier leakiness, mild diarrhea, and epithelial damage, especially in the proximal colon. Mice exhibited shifted differentiation from enterocytes to goblet cells, displayed longer crypts and an increased number of Ki67 + transit-amplifying cells in the colon. Significant proproliferative and regenerative signaling occurred in the IL-22, STAT3, and pRb pathways, with minor effects on inflammatory parameters, which, however, increased in aging mice. Importantly, colonocyte K8 deletion induced a dramatically increased sensitivity to azoxymethane-induced tumorigenesis. In conclusion, intestinal epithelial K8 plays a significant role in colonocyte epithelial integrity maintenance, proliferation regulation and tumor suppression.Graphical abstract More... »

PAGES

10

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00018-021-04081-5

DOI

http://dx.doi.org/10.1007/s00018-021-04081-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1144169275

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34951664


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39 schema:description Keratin 8 (K8) is the main intestinal epithelial intermediate filament protein with proposed roles for colonic epithelial cell integrity. Here, we used mice lacking K8 in intestinal epithelial cells (floxed K8 and Villin-Cre1000 and Villin-CreERt2) to investigate the cell-specific roles of intestinal epithelial K8 for colonocyte function and pathologies. Intestinal epithelial K8 deletion decreased K8 partner proteins, K18–K20, 75–95%, and the remaining keratin filaments were located at the colonocyte apical regions with type II K7, which decreased 30%. 2-Deoxy-2-[18F]-fluoroglucose positron emission tomography in vivo imaging identified a metabolic phenotype in the lower gut of the conditional K8 knockouts. These mice developed intestinal barrier leakiness, mild diarrhea, and epithelial damage, especially in the proximal colon. Mice exhibited shifted differentiation from enterocytes to goblet cells, displayed longer crypts and an increased number of Ki67 + transit-amplifying cells in the colon. Significant proproliferative and regenerative signaling occurred in the IL-22, STAT3, and pRb pathways, with minor effects on inflammatory parameters, which, however, increased in aging mice. Importantly, colonocyte K8 deletion induced a dramatically increased sensitivity to azoxymethane-induced tumorigenesis. In conclusion, intestinal epithelial K8 plays a significant role in colonocyte epithelial integrity maintenance, proliferation regulation and tumor suppression.Graphical abstract
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46 K7
47 K8
48 Ki67
49 STAT3
50 apical region
51 barrier leakiness
52 cell integrity
53 cell-specific role
54 cells
55 colon
56 colonocyte function
57 conclusion
58 crypts
59 damage
60 deletion
61 diarrhea
62 differentiation
63 effect
64 emission tomography
65 enterocytes
66 epithelial cell integrity
67 epithelial cells
68 epithelial damage
69 filament proteins
70 filaments
71 function
72 gut
73 inflammatory parameters
74 integrity
75 integrity maintenance
76 intermediate filament proteins
77 intestinal epithelial cells
78 keratin 8
79 keratin filaments
80 knockout
81 leakiness
82 longer crypts
83 lower gut
84 maintenance
85 metabolic phenotype
86 mice
87 mild diarrhea
88 minor effect
89 number
90 number of Ki67
91 parameters
92 partner proteins
93 pathology
94 pathway
95 phenotype
96 positron emission tomography
97 predisposes
98 proliferation regulation
99 protein
100 proximal colon
101 region
102 regulation
103 role
104 sensitivity
105 significant role
106 suppression
107 targeted deletion
108 tissue integrity
109 tomography
110 transit-amplifying cells
111 tumor suppression
112 tumorigenesis
113 vivo
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