A1 Refereed original research article in a scientific journal
Genetically Induced Mouse Model for Colon-specific Epithelial Cell Tumorigenesis Driven by Loss of K8 and Apc
Authors: Tayyab, Mina; Minkkinen, Mira M. E.; Stenvall, Carl-Gustaf A.; Polari, Lauri; Nielsen, Victor; Shah, Yatrik M.; Toivola, Diana M.
Publisher: Elsevier BV
Publication year: 2026
Journal: Cellular and molecular gastroenterology and hepatology
Article number: 101716
Volume: 20
Issue: 4
eISSN: 2352-345X
DOI: https://doi.org/10.1016/j.jcmgh.2025.101716
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1016/j.jcmgh.2025.101716
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/515800991
Self-archived copy's licence: CC BY
Self-archived copy's version: Publisher`s PDF
BACKGROUND & AIMS: Loss of keratin 8 (K8) has been shown to increase susceptibility towards colonocyte hyper-proliferation 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: Colon-specific targeting using CDX2P-CreERT2 mice was used to generate K8flox/flox; CDX2P-CreERT2 and K8flox/flox; CDX2P-CreERT2; Apcflox/+ 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: K8flox/flox; CDX2P-CreERT2 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.
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Funding information in the publication:
This project was supported by Academy of Finland project grants 315139, 332582 including InFLAMES Flagship Programme, 337531; 357911; Abo Akademi University Center of Excellence in Cellular Mechanostasis, and Solutions for Health; Medicinska understoedsfoereningen Liv och Halsa foundation (to Diana M. Toivola); NovoNordisk Foundation (NNF23OC0087039) (to Lauri Polari); Suomen Kulttuurirahasto, Varsinais Suomi Regional Fund (to Mina Tayyab); K. Albin Johansson Foundation (to Mina Tayyab and Carl-Gustaf A. Stenvall); Svenska kulturfonden (to Mina Tayyab, Mira M.E. Minkkinen, Victor Nielsen, and Carl-Gustaf A. Stenvall); Syopasaation kayttorahasto (to Mina Tayyab); Victoriastiftelsen (to Carl-Gustaf A. Stenvall); Makarna Olins Fund (to Carl-Gustaf A. Stenvall); Ida Montinin saatio (to Mina Tayyab); Abo Akademi University Foundation (to Mira M.E. Minkkinen); Doctoral Network Molecular Biosciences (to Mina Tayyab and Carl-Gustaf A. Stenvall); and NCI R01CA148828, R01CA245546, and NIDDK R01DK095201 grants (to Yatrik M. Shah); Tor, Joe, and Pentti Borg's Memorial Fund (to Diana M. Toivola and Victor Nielsen); Satakunta Hospital District (to Victor Nielsen); Satakunta Regional Fund of the Finnish Cultural Foundation (to Victor Nielsen); Oskar Oflund Foundation and Maud Kuistilas Minne Foundation (to Carl-Gustaf A. Stenvall); Abo Akademi University Solutions for Health research profile and Emil Aaltonen Foundation (to Mira M.E. Minkkinen).
