RBM47 regulates intestinal injury and tumorigenesis by modifying proliferation, oxidative response, and inflammatory pathways
Saeed Soleymanjahi, Valerie Blanc, Elizabeth A. Molitor, David M. Alvarado, Yan Xie, Vered Gazit, Jeffrey W. Brown, Kathleen Byrnes, Ta-Chiang Liu, Jason C. Mills, Matthew A. Ciorba, Deborah C. Rubin, Nicholas O. Davidson
Saeed Soleymanjahi, Valerie Blanc, Elizabeth A. Molitor, David M. Alvarado, Yan Xie, Vered Gazit, Jeffrey W. Brown, Kathleen Byrnes, Ta-Chiang Liu, Jason C. Mills, Matthew A. Ciorba, Deborah C. Rubin, Nicholas O. Davidson
View: Text | PDF
Research Article Gastroenterology Inflammation

RBM47 regulates intestinal injury and tumorigenesis by modifying proliferation, oxidative response, and inflammatory pathways

Abstract

RNA-binding protein 47 (RBM47) is required for embryonic endoderm development, but a role in adult intestine is unknown. 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. Rbm47-IKO mice exhibited increased proliferation and abnormal villus morphology and cellularity, with corresponding changes in Rbm47-IKO organoids. Rbm47-IKO mice adapted to radiation injury and were 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 were protected against colitis-associated cancer. By contrast, aged Rbm47-IKO mice developed spontaneous polyposis, and Rbm47-IKO ApcMin/+ mice manifested an increased intestinal polyp burden. RBM47 mRNA was decreased in human colorectal cancer versus paired normal tissue, along with alternative splicing of tight junction protein 1 mRNA. Public databases revealed stage-specific reduction in RBM47 expression in colorectal cancer associated independently with decreased overall survival. These findings implicate RBM47 as a cell-intrinsic modifier of intestinal growth, inflammatory, and tumorigenic pathways.

Authors

Saeed Soleymanjahi, Valerie Blanc, Elizabeth A. Molitor, David M. Alvarado, Yan Xie, Vered Gazit, Jeffrey W. Brown, Kathleen Byrnes, Ta-Chiang Liu, Jason C. Mills, Matthew A. Ciorba, Deborah C. Rubin, Nicholas O. Davidson

×

Figure 2

Constitutive intestinal Rbm47 deletion alters abundance of differentiated cell subpopulations in intestinal epithelium of young (8–14 weeks) mice.

Options: View larger image (or click on image) Download as PowerPoint
Constitutive intestinal Rbm47 deletion alters abundance of differentiate...
(A) Top: Alcian blue–stained sections of middle (left) and distal (right) small intestine in Rbm47fl/fl and Rbm47-IKO mice (scale bar: 25 μm). Bottom: goblet cell abundance (% per total cells) in villi and crypts of middle (left graph) and distal (right graph) small intestine from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 5/genotype, 30–40 villi and crypts with complete longitudinal cross-sectional view per mouse). (B) Top: Dclk1-stained sections of middle small intestine villi (left) and crypts (right) to demonstrate tuft cells in Rbm47fl/fl and Rbm47-IKO mice (scale bar: 25 μm). Bottom: tuft cell abundance (cell count/mm of border) in villi and crypts of middle small intestine from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 4/genotype, 30–40 villi and crypts with complete longitudinal cross-sectional view per mouse). (C) Top: Chromogranin A–stained sections of middle small intestine villus to demonstrate enteroendocrine cells (EEC) (red arrowheads) in Rbm47fl/fl and Rbm47-IKO mice (scale bar: 25 μm). Bottom: EEC abundance (cell count per longitudinal cross-section of villus) in middle small intestine from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 5 fl/fl and 4 IKO, 30–40 villi with complete longitudinal cross-sectional view per mouse). (D) Left: Lysozyme-stained sections of middle small intestine crypts to demonstrate Paneth cells in Rbm47fl/fl and Rbm47-IKO mice (scale bar: 20 μm). Right: Paneth cell abundance (cell count per crypt) in middle small intestine from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 5/genotype, 35–40 crypts with complete longitudinal cross-sectional view per mouse). (E) qPCR evaluation of different epithelial subpopulation cell markers in middle small intestine from young Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 4 fl/fl, 6 IKO). Data are presented as mean ± SEM; *P < 0.05, and **P < 0.01.