title: The role of KCNQ1 in mouse and human gastrointestinal cancers.
abstract: Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.
authors: 1] Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA [2] Toxicology Graduate Program, University of Minnesota, Duluth, MN, USA.
authors: B L N
authors: BL
authors: Than
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: J A C M
authors: JA
authors: Goos
authors: Department of Biostatistics and Informatics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors: A L
authors: AL
authors: Sarver
authors: College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.
authors: M G
authors: MG
authors: O'Sullivan
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors: A
authors: A
authors: Rod
authors: 1] Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA [2] Department of Obstetrics, Gynecology and Women's Health, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.
authors: T K
authors: TK
authors: Starr
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: R J A
authors: RJ
authors: Fijneman
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: G A
authors: GA
authors: Meijer
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors: L
authors: L
authors: Zhao
authors: University of Minnesota Supercomputing Institute, Minneapolis, MN, USA.
authors: Y
authors: Y
authors: Zhang
authors: Department of Obstetrics, Gynecology and Women's Health, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.
authors: D A
authors: DA
authors: Largaespada
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors: P M
authors: PM
authors: Scott
authors: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors: R T
authors: RT
authors: Cormier
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D051657:KCNQ1 Potassium Channel; D055262:Mucin-2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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