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 6

Constitutive intestinal Rbm47 deletion attenuates colitis after 3% DSS treatment.

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Constitutive intestinal Rbm47 deletion attenuates colitis after 3% DSS t...
(A) Survival rates (top), percentages of baseline body weight loss (bottom left), and disease activity scores (bottom right) of male Rbm47fl/fl and Rbm47-IKO mice treated with 3% DSS (unpaired t test, n = 14 fl/fl and 11 IKO); *P < 0.05. (B) Representative H&E-stained sections (top, scale bar: 100 μm) and microscopic histology score (bottom) of distal colon from Rbm47fl/fl and Rbm47-IKO mice treated with 3% DSS (mean ± SEM, unpaired t test, n = 7 fl/fl and 10 IKO); **P < 0.01. (C) qPCR evaluation of genes involved in antioxidative response and glutathione metabolism (top left), stem cell markers and cell proliferation genes (top right), and association between Fndc5 and Nrf2 expressions (bottom) in colons from DSS-treated male Rbm47fl/fl and Rbm47-IKO mice (mean ± SEM and unpaired t test for gene expressions, Pearson’s r test for association, n = 5/genotype); *P < 0.05, **P < 0.01. (D) Tissue content of total (left) and reduced (right) glutathione in distal colons from baseline and DSS-treated male Rbm47fl/fl and Rbm47-IKO mice (mean ± SEM, unpaired t test, n = 6/genotype for baseline and n = 8 fl/fl and 7 IKO for DSS group); *P < 0.05.