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Comparative gene expression profiling in small intestinal mucosa of Rbm47 intestine-specific knock-out and wt mice

ABSTRACT: Rationale: RNA binding protein 47 (RBM47) is required for embryonic endoderm development but a role in adult intestine is unknown. Objective: We studied intestine-specific Rbm47 knockout mice (Rbm47-IKO) following intestinal injury and made crosses into Apcmin/+ mice to examine alterations in intestinal proliferation, response to injury and tumorigenesis. We also interrogated human colorectal polyps and colon carcinoma tissue. Findings: Rbm47-IKO mice exhibit increased proliferation, abnormal villus morphology and cellularity, with corresponding changes in Rbm47-IKO organoids. Rbm47-IKO mice adapt to radiation injury and are protected against chemical-induced colitis, with Rbm47-IKO intestine showing upregulation of antioxidant and Wnt signaling pathways as well as stem cell and developmental genes. Furthermore, Rbm47-IKO mice are protected against colitis-associated cancer. By contrast, aged Rbm47-IKO mice develop spontaneous polyposis and Rbm47-IKO, Apcmin/+ mice manifest an increased intestinal polyp burden. RBM47 mRNA was decreased in human colorectal cancer versus paired normal tissue along with alternative splicing of TJP1 mRNA. Public databases revealed stage-specific reduction in RBM47 expression in colorectal cancer, associated independently with decreased overall survival. Conclusions: These findings implicate RBM47 as a cell-intrinsic modifier of intestinal growth, inflammatory and tumorigenic pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE206461 | GEO | 2023/05/31

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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Comparative gene expression profiling in small intestinal mucosa of Rbm47 intestine-specific knock-out and wt mice

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