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.
Highlights
The intestinal epithelium is maintained by a self-renewal in the crypts
Because Cre–ERT2 fusion gene activity is inducible following tamoxifen administration, this experimental system has the advantage of being able to analyze the specific function of Klf5 in the intestinal epithelial stem cells, thereby avoiding artifacts that might arise from deficiency of Klf5 throughout development [4, 28]
We found the inducible deletion of Klf5 in Lgr5þ stem cells resulted in the appearance of some dead or abnormal-looking Klf5D/D cells, whereas no such cells were observed in Klf5-positive crypt epithelia in the same mice (Fig. 1B)
Summary
The intestinal epithelium is maintained by a self-renewal in the crypts. In this process, the resident stem cells located in the crypt base produce proliferating progenitors, transit-amplifying cells, which move upward as coherent columns [1, 2]. Intestinal epithelia include short-lived progenitors, long-lived progenitors, columnar cell progenitors, and pluripotential stem cells [3]. The stem-cell pools include Lgr5þ crypt-base columnar (CBC) cells and Lrig1þ cells at the bases of crypts, and Hopxþ or Bmi1þ cells located at the þ4 position from the bottom of the crypts [1, 4,5,6,7,8].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
