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

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

Cellular and Molecular Gastroenterology and Hepatology (Jan 2019)

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

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

Affiliations

Nicola Currey: Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Zeenat Jahan: Garvan Institute of Medical Research, Sydney, New South Wales, Australia
C. Elizabeth Caldon: 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
Phuong N. Tran: 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
Fahad Benthani: 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
Penelope De Lacavalerie: 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
Daniel L. Roden: 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
Brian S. Gloss: 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
Claudia Campos: Instituto Gulbenkian de Ciência, Oeiras, Portugal
Elaine G. Bean: ACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, Australia
Amanda Bullman: ACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, Australia
Saskia Reibe-Pal: Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Marcel E. Dinger: 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
Mark A. Febbraio: 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
Stephen J. Clarke: Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia
Jane E. Dahlstrom: ACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, Australia
Maija R.J. Kohonen-Corish: 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; Correspondence Address correspondence to: Maija Kohonen-Corish, PhD, Microbiome Research Centre, University of New South Wales Sydney, Level 2 Clinical Sciences (WR Pitney) Building, St George Hospital, Short Street, Kogarah New South Wales 2217, Australia. fax: (61) 2-91133998.

Journal volume & issue: Vol. 7, no. 4
pp. 819 – 839

Abstract

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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 (MccΔIEC) or in the whole body (MccΔ/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 MccΔIEC 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: E2F Targets, DNA Repair, IFNγ-Induced GTPases, CMS4

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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