CFTR is a tumor suppressor gene in murine and human intestinal cancer

Autor: Gerrit A. Meijer, Remond J.A. Fijneman, B L N Than, David A. Largaespada, Robert T. Cormier, A Niemczyk, A Schumann, Janneke F. Linnekamp, Louis Vermeulen, A Rod, Craig A. Hodges, Juan E. Abrahante, Ying Zhang, V Bruner, Michael G. O’Sullivan, Timothy K. Starr, Jan Paul Medema, T Luczak, E Van den Broek, Patricia M. Scott
Přispěvatelé: Other departments, Center of Experimental and Molecular Medicine, Radiotherapy, Amsterdam Gastroenterology Endocrinology Metabolism, Medical oncology, Pathology, CCA - Cancer biology, Pediatric surgery, CCA - Cancer biology and immunology, Graduate School, CCA -Cancer Center Amsterdam, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
congenital
hereditary
and neonatal diseases and abnormalities
Tumor suppressor gene
Colon
Cystic Fibrosis Transmembrane Conductance Regulator
Cystic fibrosis
Disease-Free Survival
Article
Mice
03 medical and health sciences
0302 clinical medicine
Genetics
medicine
Animals
Humans
Genes
Tumor Suppressor
Molecular Biology
Tissue homeostasis
Regulation of gene expression
biology
Microarray analysis techniques
Wnt signaling pathway
respiratory system
medicine.disease
Cystic fibrosis transmembrane conductance regulator
digestive system diseases
respiratory tract diseases
Gene Expression Regulation
Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
Immunology
Knockout mouse
biology.protein
Cancer research
Colorectal Neoplasms
Gene Deletion
Signal Transduction
Zdroj: Oncogene, 36(24). Nature Publishing Group
Oncogene, 35(32), 4191-4199. Nature Publishing Group
Oncogene, 35(32), 4179-4187. Nature Publishing Group
Than, B L N, Linnekamp, J F, Starr, T K, Largaespada, D A, Rod, A, Zhang, Y, Bruner, V, Abrahante, J, Schumann, A, Luczak, T, Niemczyk, A, O'Sullivan, M G, Medema, J P, Fijneman, R J A, Meijer, G A, Van den Broek, E, Hodges, C A, Scott, P M, Vermeulen, L & Cormier, R T 2016, ' CFTR is a tumor suppressor gene in murine and human intestinal cancer ', Oncogene, vol. 35, no. 32, pp. 4191-4199 . https://doi.org/10.1038/onc.2015.483
ISSN: 0950-9232
DOI: 10.1038/onc.2015.483
Popis: CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival.
Databáze: OpenAIRE
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