Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and Cancer
| Autor: | Saskia Reibe-Pal, Mark A. Febbraio, Amanda Bullman, Brian S. Gloss, Elaine G. Bean, C. Elizabeth Caldon, Stephen Clarke, Marcel E. Dinger, Nicola Currey, Daniel L. Roden, Maija R.J. Kohonen-Corish, Phuong N. Tran, Penelope De Lacavalerie, Fahad Benthani, Jane E. Dahlstrom, Claudia Guimarães Camargo Campos, Zeenat Jahan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
RB
retinoblastoma WT wild type 0301 basic medicine Male DNA Repair Colorectal cancer CMS4 medicine.disease_cause GTP Phosphohydrolases BrdU bromodeoxyuridine Transcriptome AHR aryl hydrocarbon receptor 0302 clinical medicine GSEA gene set enrichment analysis GTPase guanosine triphosphatase CMS4 consensus molecular subtype 4 DSS dextran sodium sulfate R reverse beta Catenin Original Research Mice Knockout IBD inflammatory bowel disease E2F Targets Gastroenterology food and beverages CHK checkpoint kinase Cadherins 3. Good health Up-Regulation Gene Expression Regulation Neoplastic IFNγ-Induced GTPases Knockout mouse qPCR quantitative polymerase chain reaction 030211 gastroenterology & hepatology Female Colorectal Neoplasms MEF mouse embryo fibroblast DNA damage DNA repair Colon CAC colitis-associated cancer F forward IFNγ interferon γ Down-Regulation SSB DNA single-strand break MMR mismatch repair EMT epithelial mesenchymal transition γH2AX gamma histone 2AX Biology Genes MCC cDNA complementary DNA 03 medical and health sciences Interferon-gamma medicine Gene silencing Animals lcsh:RC799-869 KD knockdown UPL Universal Probe Library Inflammation KO knockout Hepatology Cancer medicine.disease NT nontargeted digestive system diseases Mice Inbred C57BL MCC mutated in colorectal cancer Disease Models Animal 030104 developmental biology Cancer research lcsh:Diseases of the digestive system. Gastroenterology Carcinogenesis Gene Deletion |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 7, Iss 4, Pp 819-839 (2019) |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|