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

Oncogene volume 35, pages 4191–4199 (2016)Cite this article

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A Corrigendum to this article was published on 13 February 2017

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 ApcMin 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.

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Acknowledgements

This work was supported by the grant from the National Cancer Institute (NCI) to RC and DL (NCI R01 CA134759-01A1); grant from the Mezin-Koats Colon Cancer Research fund to TS; grant from NCI to support the University of Minnesota Masonic Cancer Center (NCI P30-CA775598); grant from the Whiteside Institute for Clinical Research to RC and PS; grant from the University of Minnesota Foundation to RC, TS and DL; grant from Essentia Health Systems to RC; grant from the AICR (14–1164) to LV; grants from the Dutch Cancer Society (UVA2011–4969, UVA2014–7245) to LV; NWO gravitation grant to JL; grants from the National Cancer Institute to TS (NCI 5R00CA151672-04 and P30-CA77598). We also wish to thank Drs Mitchell Drumm and Craig Hodges of CWRU for providing the Cftr mutant mice.

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Author notes

  1. B L N Than

    Present address: 12Current address: Division of Gastroenterology & Hepatology, Weill Cornell Medical College, New York, NY, USA.,

  2. B L N Than and J F Linnekamp: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA

    B L N Than, A Rod, V Bruner, A Schumann, T Luczak, A Niemczyk, P M Scott & R T Cormier

  2. Laboratory of Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands

    J F Linnekamp, J P Medema & L Vermeulen

  3. Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA

    T K Starr & J Abrahante

  4. Department of Obstetrics, Gynecology and Women’s Health, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA

    T K Starr

  5. Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

    D A Largaespada

  6. University of Minnesota Supercomputing Institute, Minneapolis, MN, USA

    Y Zhang

  7. College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA

    M G O'Sullivan

  8. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    R J A Fijneman, G A Meijer & E Van den Broek

  9. Netherlands Cancer Institute, Amsterdam, the Netherlands

    R J A Fijneman & G A Meijer

  10. Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    C A Hodges

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  1. B L N Than
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Correspondence to P M Scott, L Vermeulen or R T Cormier.

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Than, B., Linnekamp, J., Starr, T. et al. CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 35, 4191–4199 (2016). https://doi.org/10.1038/onc.2015.483

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