KLF5 mediates the hyper-proliferative phenotype of the intestinal epithelium in mice with intestine-specific endogenous K-Ras expression.

Oncogenic activation is a common mutational event in colorectal cancer. We previously showed that transcription factor, Krüppel-like factor 5 (KLF5), contributes to intestinal polyposis in mice with activation. At 14 months of age, mice developed small intestinal and colonic hyperplastic polyps while had none. The intestinal crypts of mice contained a higher number of mitotic figures and increased crypt heights compared to controls. The intestinal epithelium of mice showed prolific KLF5 expression throughout and above the elongated crypts. In contrast, KLF5 expression was limited to the upper crypt region in the controls. The levels of K-Ras effectors were significantly increased in as compared to controls. The mice showed decreased survival upon treatment with azoxymethane (AOM) as compared to controls. Furthermore, loss of one of alleles reduced levels of K-Ras effector proteins and prevented mortality of mice upon AOM treatment. The mice spontaneously develop hyperplastic intestinal polyps and display a hyper-proliferative intestinal phenotype with elongated crypts, increased numbers of mitotic figures, elevated expression of KLF5, and other pro-proliferative targets. Induction of colonic tumorigenesis with AOM is detrimental to mice that is in part dependent of KLF5.