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
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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

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Figure 1

Constitutive intestinal Rbm47 deletion enhances the proliferation capacity and anatomical development of intestinal epithelium in young (8–14 weeks) mice.

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Constitutive intestinal Rbm47 deletion enhances the proliferation capaci...
(A) Small intestine (top) and colon (bottom) length in Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 55 fl/fl, 37 IKO for small intestine and 43 fl/fl, 24 IKO for colon). (B) Top: regional sections of small intestine and colon from Rbm47fl/fl and Rbm47-IKO mice (scale bar: 50 μm). Bottom: Crypt depth in Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 6/genotype, 30–40 crypts with longitudinal cross-sectional view per mouse). (C) Left: Regional BrdU-positive abundance (% per total crypt cells) in small intestine and colon from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 6/genotype, 20–30 crypts with complete longitudinal cross-sectional view per mouse). Right: BrdU-stained sections of middle small intestine crypts (scale bar: 25 μm). (D) Left: Cyclin D1–positive abundance (% per total crypt cells) in jejunum and colon from young Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 5/genotype, 20–30 crypts with longitudinal cross-sectional view per mouse); Right: Cyclin D1-stained sections of middle small intestine crypts (scale bar: 25 μm). (E) Left: regional crypt fission in small intestine from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 6/genotype, 200 crypts with longitudinal cross-sectional view per mouse per section). Right: H&E-stained view of crypt fission (scale bar: 50 μm). (F) Transmission electron microscopic sections exhibiting length (left) and cross-sectional density (middle) of microvilli (scale bar: 500 nm) and scanning electron microscopic sections of villi (right, scale bar: 100 μm) in middle small intestine of young mice. (G) Left: Length (top) and density (bottom) of microvilli in middle small intestine from Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 3/genotype, 75–100 microvilli per mouse). Right: middle small intestine villi width in Rbm47fl/fl and Rbm47-IKO mice (unpaired t test, n = 6/genotype, 60–80 villi per mouse). Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.