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Expression data from small intestine crypts of Zfp148gt/+APCMin/+ and Zfp148+/+APCMin/+ mice

ABSTRACT: The transcription factor Zinc finger protein 148 (Zfp148) interacts physically with the tumor suppressor p53, but the siginficance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesized that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas.

ORGANISM(S): Mus musculus

PROVIDER: GSE77773 | GEO | 2016/02/10

SECONDARY ACCESSION(S): PRJNA311516

REPOSITORIES: GEO

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Project description:To identify the precise molecular mechanisms that could contribute to the increase in colon carcinogenesis, microarray gene expression analysis was performed on colon RNA isolated from 5-week-old VhlF/F and VhlΔIE, VhlΔIE/Apcmin/+ and VhlF/F/Apcmin/+ mice. Hypoxia-inducible factor (HIF) is a key modulator of the transcriptional response to hypoxia and is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. Intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and Hif-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue, however tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, BrdU incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis demonstrated that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings demonstrate that a chronic increase in HIF-2α in the colon initiates pro-tumorigenic signaling which may have important implications in developing preventive and therapeutic strategies for colon cancer. Global gene expression profiling in colon RNAs isolated from 5-week-old VhlF/F (n=4, Shah 001), VhlF/F/Apcmin/+(n=3, Shah 003), VhlΔIE (n=3, Shah 002) and VhlΔIE/Apcmin/+ mice (n=5, Shah 004).

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Expression data from small intestine crypts of Zfp148gt/+APCMin/+ and Zfp148+/+APCMin/+ mice

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