KLF5 regulates the integrity and oncogenicity of intestinal stem cells

Takeo Nakaya, Seishi Ogawa, Ichiro Manabe, Masami Tanaka, Masashi Sanada, Toshiro Sato, Makoto M Taketo, Kazuki Nakao, Hans Clevers, Masashi Fukayama, Masahiko Kuroda, Ryozo Nagai

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)2882-91
Aantal pagina's10
TijdschriftCancer Research
Volume74
Nummer van het tijdschrift10
DOI's
StatusGepubliceerd - 15 mei 2014

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