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Krüppel-like factor 5 is a crucial mediator of intestinal tumorigenesis in mice harboring combined Apc Min and KRAS V12 mutations

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Author(s): Nandan Mandayam | Ghaleb Amr | McConnell Beth | Patel Nilesh | Robine Sylvie | Yang Vincent

Journal: Molecular Cancer
ISSN 1476-4598

Volume: 9;
Issue: 1;
Start page: 63;
Date: 2010;
Original page

ABSTRACT
Abstract Background Both mutational inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene and activation of the KRAS oncogene are implicated in the pathogenesis of colorectal cancer. Mice harboring a germline Apc Min mutation or intestine-specific expression of the KRAS V12 gene have been developed. Both mouse strains develop spontaneous intestinal tumors, including adenoma and carcinoma, though at a different age. The zinc finger transcription factor Krüppel-like factor 5 (KLF5) has previously been shown to promote proliferation of intestinal epithelial cells and modulate intestinal tumorigenesis. Here we investigated the in vivo effect of Klf5 heterozygosity on the propensity of Apc Min /KRAS V12 double transgenic mice to develop intestinal tumors. Results At 12 weeks of age, Apc Min /KRAS V12 mice had three times as many intestinal tumors as Apc Min mice. This increase in tumor number was reduced by 92% in triple transgenic Apc Min /KRAS V12/Klf5 +/- mice. The reduction in tumor number in Apc Min /KRAS V12/Klf5 +/- mice was also statistically significant compared to Apc Min mice alone, with a 75% decrease. Compared with Apc Min /KRAS V12, tumors from both Apc Min /KRAS V12/Klf5 +/- and Apc Min mice were smaller. In addition, tumors from Apc Min mice were more distally distributed in the intestine as contrasted by the more proximal distribution in Apc Min /KRAS V12 and Apc Min /KRAS V12/Klf5 +/- mice. Klf5 levels in the normal-appearing intestinal mucosa were higher in both Apc Min and Apc Min /KRAS V12 mice but were attenuated in Apc Min /KRAS V12/Klf5 +/- mice. The levels of β-catenin, cyclin D1 and Ki-67 were also reduced in the normal-appearing intestinal mucosa of Apc Min /KRAS V12/Klf5 +/- mice when compared to Apc Min /KRAS V12 mice. Levels of pMek and pErk1/2 were elevated in the normal-appearing mucosa of Apc Min /KRAS V12 mice and modestly reduced in ApcMin/KRAS V12/Klf5 +/- mice. Tumor tissues displayed higher levels of both Klf5 and β-catenin, irrespective of the mouse genotype from which tumors were derived. Conclusions Results of the current study confirm the cumulative effect of Apc loss and oncogenic KRAS activation on intestinal tumorigenesis. The drastic reduction in tumor number and size due to Klf5 heterozygosity in Apc Min /KRAS V12 mice indicate a critical function of KLF5 in modulating intestinal tumor initiation and progression.
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