KLF5 mediates the hyper-proliferative phenotype of the intestinal epithelium in mice with intestine-specific endogenous K-Ras^G12D expression

Oncogenic K-Ras 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 K-Ras activation. At 14 months of age, Villin-Cre/LSL-K-Ras^G12D mice developed small intestinal and colonic hyperplastic polyps while LSL-K-Ras^G12D had none. The intestinal crypts of Villin-Cre/LSL-K-Ras^G12D mice contained a higher number of mitotic figures and increased crypt heights compared to controls. The intestinal epithelium of Villin-Cre/LSL-K-Ras^G12D 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 Villin-Cre/LSL-K-Ras^G12D as compared to controls. The Villin-Cre/LSL-K-Ras^G12D mice showed decreased survival upon treatment with azoxymethane (AOM) as compared to controls. Furthermore, loss of one of Klf5 alleles reduced levels of K-Ras effector proteins and prevented mortality of Villin-Cre/LSL-K-Ras^G12D mice upon AOM treatment. The Villin-Cre/LSL-K-Ras^G12D 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 Villin-Cre/LSL-K-Ras^G12D mice that is in part dependent of KLF5.