Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and Cancer

Nicola Currey; Zeenat Jahan; C Elizabeth Caldon; Phuong N Tran; Fahad Benthani; Penelope De Lacavalerie; Daniel L Roden; Brian S Gloss; Claudia Campos; Elaine G Bean; Amanda Bullman; Saskia Reibe-Pal; Marcel E Dinger; Mark A Febbraio; Stephen J Clarke; Jane E Dahlstrom; Maija R J Kohonen-Corish

doi:10.1016/j.jcmgh.2019.01.009

Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and Cancer

Cell Mol Gastroenterol Hepatol. 2019;7(4):819-839. doi: 10.1016/j.jcmgh.2019.01.009. Epub 2019 Mar 2.

Authors

Nicola Currey¹, Zeenat Jahan¹, C Elizabeth Caldon², Phuong N Tran², Fahad Benthani², Penelope De Lacavalerie², Daniel L Roden², Brian S Gloss², Claudia Campos³, Elaine G Bean⁴, Amanda Bullman⁴, Saskia Reibe-Pal¹, Marcel E Dinger², Mark A Febbraio², Stephen J Clarke⁵, Jane E Dahlstrom⁴, Maija R J Kohonen-Corish⁶

Affiliations

¹ Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
² Garvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
³ Instituto Gulbenkian de Ciência, Oeiras, Portugal.
⁴ ACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, Australia.
⁵ Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia.
⁶ Garvan Institute of Medical Research, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Sydney, New South Wales, Australia; Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: m.corish@garvan.org.au.

Abstract

Background & aims: The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon.

Methods: We generated knockout mice with deletion of Mcc in the colonic/intestinal epithelial cells (Mcc^ΔIEC) or in the whole body (Mcc^Δ/Δ). Drug-induced lesions were analyzed by transcriptome profiling (at 10 weeks) and histopathology (at 20 weeks). Cell-cycle phases and DNA damage proteins were analyzed by flow cytometry and Western blot of hydrogen peroxide-treated mouse embryo fibroblasts.

Results: Transcriptome profiling of the lesions showed a strong response to colon barrier destruction, such as up-regulation of key inflammation and cancer-associated genes as well as 28 interferon γ-induced guanosine triphosphatase genes, including the homologs of Crohn's disease susceptibility gene IRGM. These features were shared by both Mcc-expressing and Mcc-deficient mice and many of the altered gene expression pathways were similar to the mesenchymal colorectal cancer subtype known as consensus molecular subtype 4 (CMS4). However, Mcc deletion was required for increased carcinogenesis in the lesions, with adenocarcinoma in 59% of Mcc^ΔIEC compared with 19% of Mcc-expressing mice (P = .002). This was not accompanied by hyperactivation of β-catenin, but Mcc deletion caused down-regulation of DNA repair genes and a disruption of DNA damage signaling.

Conclusions: Loss of Mcc may promote cancer through a failure to repair inflammation-induced DNA damage. We provide a comprehensive transcriptome data set of early colorectal lesions and evidence for the in vivo significance of MCC silencing in colorectal cancer.

Keywords: CMS4; DNA Repair; E2F Targets; IFNγ-Induced GTPases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cadherins / metabolism
Colon / drug effects
Colon / pathology
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
DNA Repair / genetics
Disease Models, Animal
Down-Regulation / drug effects
Down-Regulation / genetics
Female
GTP Phosphohydrolases / metabolism
Gene Deletion*
Gene Expression Regulation, Neoplastic / drug effects
Genes, MCC*
Inflammation / genetics*
Inflammation / pathology
Interferon-gamma / pharmacology
Male
Mice, Inbred C57BL
Mice, Knockout
Up-Regulation / drug effects
Up-Regulation / genetics
beta Catenin / metabolism

Substances

Cadherins
beta Catenin
Interferon-gamma
GTP Phosphohydrolases