Journal Article

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

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

2022

Overview

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-CreER t2 ) 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-[ 18 F]-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

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Aging / Aging - pathology / Animals / Azoxymethane / Biochemistry / Biomedical and Life Sciences / Biomedicine / carcinogenesis / Carcinogenesis - metabolism / Carcinogenesis - pathology / Cell Biology / Cell Differentiation / Cell Proliferation / Colon / Colon - pathology / Colorectal cancer / Crypts / Diarrhea / Diarrhea - complications / Diarrhea - pathology / Down-Regulation / Enterocytes / Epithelial cells / Epithelial Cells - metabolism / Epithelium / Filaments / Fluorodeoxyglucose F18 - metabolism / Gene Deletion / Gene Targeting / Goblet cells / Goblet Cells - metabolism / Inflammation / Inflammation - pathology / Integrases - metabolism / Integrity / Interleukin 22 / Intestine / Intestines - pathology / Keratin / Keratin-8 - deficiency / Keratin-8 - genetics / Life Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Microfilament Proteins - metabolism / neoplasms / Original / Original Article / Permeability / Phenotype / Phenotypes / Positron emission / Positron emission tomography / Proteins / Stat3 protein / Tumor suppression / Tumorigenesis