Genetically Induced Mouse Model for Colon-specific Epithelial Cell Tumorigenesis Driven by Loss of K8 and Apc
Year: 2025
Type: article
Abstract: BACKGROUND & AIMS: Loss of keratin 8 (K8) has been shown to increase susceptibility towards colonocyte hyperproliferation and tumorigenesis. However, most colorectal cancer (CRC) mouse models require carcinogen, develop small intestinal tumors, or have a long latency period. The aim was to establish a genetic, colon-specific, and more human-like CRC model driven by loss of K8 and adenomatous polyposis coli (Apc). METHODS: mice. Disease activity was monitored, and colon was analyzed for tumor burden and histopathology over time. Keratin expression, inflammation, proliferation, cell polarity, colonocyte populations, and cell division symmetry were assessed using immunoblotting and immunofluorescence analysis. This data was compared with K8 expression analysis in patients with CRC and in UALCAN database. RESULTS: mice develop mild diarrhea and express reduced K8 and partner keratins in a mosaic pattern in the colonic epithelium. K8-negative colon areas display increased crypt loss and more inflammation predominantly in the proximal colon. Increased colonocyte proliferation is observed throughout the colon. Impaired cell polarity and higher number of stem and progenitor cells with a shift towards asymmetric cell division in K8-negative areas of the distal colon highlight a pro-tumorigenic environment. Mice with additional monoallelic Apc inactivation show colon tumorigenesis and epithelial to mesenchymal transition distally. In patients with CRC, tumor K8 expression is decreased independent of disease type and stage, age, or gender. CONCLUSIONS: Genetic colon-specific mouse model with loss of K8 and Apc adequately resembles human CRC. This study identifies anti-tumorigenic protective roles of colonocyte K8 in the colon.
Institutions: Åbo Akademi University, University of Michigan, Michigan Medicine
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Funders: Northwestern University, Ida Montinin Säätiö, Victoriastiftelsen, Medicinska Understödsföreningen Liv och Hälsa, Maud Kuistilan Muistosäätiö, Academy of Finland, Suomen Kulttuurirahasto, Emil Aaltosen Säätiö, Turun Yliopisto, Oskar Öflunds Stiftelse, Svenska Kulturfonden, Stiftelsen för Åbo Akademi, Åbo Akademi, K. Albin Johanssons Stiftelse, Novo Nordisk Fonden, Syöpäsäätiö, Novo Nordisk Foundation Center for Basic Metabolic Research, Biocenter Finland, National Institutes of Health, Varsinais-Suomen Rahasto, Satakunnan Rahasto, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Understanding the mechanisms of iron addiction in colon cancer, InFLAMES: Innovation Ecosystem based on the Immune System, G3555624240, InFLAMES: Innovation Ecosystem based on the Immune System, G464308390, G5087596548, A colon-specific mouse model for colorectal cancer: Keratins as tumor suppressors and guardians of intestinal health, Control of iron absorption by intestinal HIF2 in iron and hematological disorders
OpenAlex ID: W7117243229