The role of KCNQ1 in mouse and human gastrointestinal cancers
| Autor: | Jeroen A.C.M. Goos, Bich L. N. Than, Gerrit A. Meijer, A Rod, David A. Largaespada, Aaron L. Sarver, Remond J.A. Fijneman, Lei Zhao, Michael G. O’Sullivan, Timothy K. Starr, Ying Zhang, Patricia M. Scott, Robert T. Cormier |
|---|---|
| Přispěvatelé: | Radiology and nuclear medicine, Pathology, CCA - Oncogenesis |
| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research endocrine system diseases Tumor suppressor gene Microarray tumor suppressor Colorectal cancer Cellular detoxification Cystic Fibrosis Transmembrane Conductance Regulator colorectal cancer Mucin 2 Biology Article Mice 03 medical and health sciences 0302 clinical medicine Intestine Small Genetics medicine Animals Humans Molecular Biology Gastrointestinal Neoplasms Neoplasm Staging 030304 developmental biology Mice Knockout Mucin-2 0303 health sciences KCNQ1 urogenital system Gene Expression Profiling Cancer Prognosis medicine.disease 3. Good health Gene expression profiling Disease Models Animal Phenotype medicine.anatomical_structure 030220 oncology & carcinogenesis KCNQ1 Potassium Channel Immunology Paneth cell Disease Progression Cancer research Female Signal Transduction |
| Zdroj: | Oncogene Oncogene, 33(29), 3861-3868. Nature Publishing Group Than, B L N, Goos, J A C M, Sarver, A L, O'Sullivan, MG, Rod, A, Starr, T K, Fijneman, R J A, Meijer, G A, Zhao, L, Zhang, Y, Largaespada, D A, Scott, P M & Cormier, R T 2014, ' The role of KCNQ1 in mouse and human gastrointestinal cancers ', Oncogene, vol. 33, no. 29, pp. 3861-3868 . https://doi.org/10.1038/onc.2013.350 |
| ISSN: | 0950-9232 |
| DOI: | 10.1038/onc.2013.350 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|