title: CFTR is a tumor suppressor gene in murine and human intestinal cancer.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: B L N
authors.initials: BL
authors.lastname: Than
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Linnekamp
authors.affiliation: Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.|Department of Obstetrics, Gynecology and Women's Health, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Starr
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rod
authors.affiliation: University of Minnesota Supercomputing Institute, Minneapolis, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bruner
authors.affiliation: Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Abrahante
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Schumann
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: T
authors.initials: T
authors.lastname: Luczak
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: J
authors.lastname: Walter
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Niemczyk
authors.affiliation: College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: R J A
authors.initials: RJ
authors.lastname: Fijneman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Van den Broek
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hodges
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Scott
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: L
authors.identifier: 0000-0002-6066-789X
authors.initials: L
authors.lastname: Vermeulen
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Cormier
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D018572:Disease-Free Survival; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D009154:Mutation; D015398:Signal Transduction
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator