@article{72a2dc91945f41ebb4f834eedd4a0b7d,
title = "Targeted deletion of keratin 8 in intestinal epithelial cells disrupts tissue integrity and predisposes to tumorigenesis in the colon",
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: [Figure not available: see fulltext.]",
keywords = "Barrier, Colon cancer, Goblet cell, Notch, Proliferation, Tumorigenesis, Villin-Cre",
author = "Stenvall, {Carl Gustaf A.} and Mina Tayyab and Gr{\"o}nroos, {Tove J.} and Ilom{\"a}ki, {Maria A.} and Keijo Viiri and Ridge, {Karen M.} and Lauri Polari and Toivola, {Diana M.}",
note = "Funding Information: This work was financed by the Academy of Finland 315139/332582 (DMT) and #310011 (KV), Sigrid Juselius Foundation, {\AA}AU Center of Excellence of Cellular Mechanostasis, EuroCellNet COST Action (CA15214) (DMT); by Medicinska Underst{\"o}dsf{\"o}reningen Liv och H{\"a}lsa Foundation (DMT; CGAS); by Turku Doctoral Programme in Molecular Biosciences at {\AA}AU, Swedish Cultural Foundation, Victoriastiftelsen, Agneta and Carl-Erik Olin foundation, and K. Albin Johansson foundation (CGAS). We thank all the other members of the Toivola laboratory, especially Jimmy Fagersund, Akmal Nipu, and Frank Weckstr{\"o}m for support in the laboratory. Imaging was performed at the Cell Imaging and Cytometry Core, Turku Bioscience Center, University of Turku, {\AA}bo Akademi University and Biocenter Finland, and sample preparation for histology was done at the Turku Center for Disease Modeling histology service unit at University of Turku, Finland. Funding Information: This work was financed by the Academy of Finland 315139/332582 (DMT) and #310011 (KV), Sigrid Juselius Foundation, ?AU Center of Excellence of Cellular Mechanostasis, EuroCellNet COST Action (CA15214) (DMT); by Medicinska Underst?dsf?reningen Liv och H?lsa Foundation (DMT; CGAS); by Turku Doctoral Programme in Molecular Biosciences at ?AU, Swedish Cultural Foundation, Victoriastiftelsen, Agneta and Carl-Erik Olin foundation, and K. Albin Johansson foundation (CGAS). We thank all the other members of the Toivola laboratory, especially Jimmy Fagersund, Akmal Nipu, and Frank Weckstr?m for support in the laboratory. Imaging was performed at the Cell Imaging and Cytometry Core, Turku Bioscience Center, University of Turku, ?bo Akademi University and Biocenter Finland, and sample preparation for histology was done at the Turku Center for Disease Modeling histology service unit at University of Turku, Finland.",
year = "2021",
doi = "10.1007/s00018-021-04081-5",
language = "English",
volume = "79",
journal = "CELLULAR AND MOLECULAR LIFE SCIENCES",
issn = "1420-682X",
publisher = "Springer Verlag",
}
