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 9

RBM47 expression and alternative splicing of Tjp1/Zo1 mRNA are downregulated with prognostic impact in patients with colorectal cancer.

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RBM47 expression and alternative splicing of Tjp1/Zo1 mRNA are downregu...
(A) RBM47 mRNA expression in uninvolved and paired tumor tissue samples from patients with colorectal cancer (paired t test, n = 24); ****P < 0.0001. (B) RBM47 mRNA expression in normal versus adenocarcinoma colon (top) (n = 34 normal and 36 adenocarcinoma) and normal versus adenoma colon (bottom) (n = 32 normal and 32 adenoma) samples extracted from NCBI GEO repositories GSE20916 and GSE8671, respectively. (C) qPCR evaluation of Zo1+20 expression in uninvolved and paired tumor tissue samples from patients with colorectal cancer (paired t test, n = 22); *P < 0.05. (D) Correlation of Rbm47 and Zo1+20 expressions in uninvolved (left) and tumor (right) tissue samples from patients with colorectal cancer (Pearson’s r correlation test, n = 22 uninvolved and 24 tumor tissue samples). (E) RBM47 (left) and Zo1+20 (right) mRNA expressions in colorectal cancer patients with low, 0, and high, 1–2, N stage (mean ± SEM, unpaired t test, n = 8–10 low stage and 7 high stage); *P < 0.05. (F) RBM47 mRNA expression in colorectal cancer patients with different N (left) and TNM (right) stages (mean ± SEM, ANOVA test, N stage n = N0 340, N1 141, N2 108; TNM stage n = TNM1 103, TNM2 220, TNM3 170, TNM4 85); ***P < 0.001, ****P < 0.0001. RSEM, RNA-Seq by Expectation Maximization software. (G) Overall (top) and progression-free (bottom) survival rates of colorectal cancer patients with different levels of tumoral Rbm47 mRNA expression (Kaplan-Meier curves and simple Cox proportional-hazard model, n = 141 low expression, 282 moderate expression, 141 high expression). For F and G, data were extracted from PanCancer colorectal adenocarcinoma database of The Cancer Genome Atlas.