Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X1930013X |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary Cellular and Molecular Gastroenterology and Hepatology |
| author_facet |
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 |
| author_sort |
Nicola Currey |
| title |
Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary |
| title_short |
Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary |
| title_full |
Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary |
| title_fullStr |
Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary |
| title_full_unstemmed |
Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummary |
| title_sort |
mouse model of mutated in colorectal cancer gene deletion reveals novel pathways in inflammation and cancersummary |
| publisher |
Elsevier |
| series |
Cellular and Molecular Gastroenterology and Hepatology |
| issn |
2352-345X |
| publishDate |
2019-01-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S2352345X1930013X |
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doaj-3f5a2d0c39a64c9b94fae8baddfca8d12020-11-25T02:20:56ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2019-01-0174819839Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and CancerSummaryNicola Currey0Zeenat Jahan1C. Elizabeth Caldon2Phuong N. Tran3Fahad Benthani4Penelope De Lacavalerie5Daniel L. Roden6Brian S. Gloss7Claudia Campos8Elaine G. Bean9Amanda Bullman10Saskia Reibe-Pal11Marcel E. Dinger12Mark A. Febbraio13Stephen J. Clarke14Jane E. Dahlstrom15Maija R.J. Kohonen-Corish16Garvan Institute of Medical Research, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaInstituto Gulbenkian de Ciência, Oeiras, PortugalACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, AustraliaACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaGarvan Institute of Medical Research, Sydney, New South Wales, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, AustraliaRoyal North Shore Hospital, University of Sydney, Sydney, New South Wales, AustraliaACT Pathology, The Canberra Hospital, Australian National University Medical School, Canberra, Australian Capital Territory, AustraliaGarvan 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.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, CMS4http://www.sciencedirect.com/science/article/pii/S2352345X1930013X |