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Improved Swiss-rolling Technique for Intestinal Tissue Preparation for Immunohistochemical and Immunofluorescent Analyses
Published on: July 13, 2016
KLF5 regulates the integrity and oncogenicity of intestinal stem cells
Takeo Nakaya1, Seishi Ogawa2, Ichiro Manabe2
1Authors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke, Tochigi, Japan; and Hubrecht Institute and KNAW, Utrecht, the NetherlandsAuthors' Affiliations: Department of Molecular Pathology and Translational Research Unit, Tokyo Medical University; Cancer Genomics Project; Departments of Pathology, and Cardiovascular Medicine; Animal Resources, Graduate School of Medicine, University of Tokyo; Honeybee Science Research Center, Tamagawa University; Department of Gastroenterology, School of Medicine, Keio University, Tokyo; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto; Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe; Jichi Medical University, Shimotsuke,
Abstract:
The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5(+) crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5(+) stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of β-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of β-catenin in Lgr5(+) stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/β-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer.
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