Stress Response Protein RBM3 Promotes the Development of Colitis-associated Cancer

Background: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Stress response proteins Cirp and heat shock protein A4 are involved in the refractory clinical course and development of CAC. RNAbinding motif protein 3 (RBM3) is induced in response to various stresses and is upregulated in several cancers. However, the role of RBM3 in CAC is unclear. Methods: We assessed RBM3 expression and function in 263 human intestinal mucosa samples from patients with IBD and in Rbm3-deficient (Rbm3(-/-)) mice. Results: Expression of RBM3 was correlated with the expression of stress response proteins Cirp, heat shock protein A4, and HSP27 in the colonic mucosa of patients with IBD. Significant correlation was observed between the expression of RBM3 and that of Bcl-xL or stem cell markers. RBM3 expression increased and significantly correlated with R-spondin expression in the colonic mucosa of patients with refractory IBD, a condition associated with increased cancer risk, and RBM3 was overexpressed in human CACs. In the murine CAC model, Rbm3 deficiency decreased R-spondin and Bcl-xL expression and increased apoptotic cell number in the colonic mucosa, leading to reduced tumor multiplicity. Transplantation of wild-type and Rbm3(-/-) bone marrow did not alter tumor burden, indicating the importance of RBM3 in epithelial cells. Conclusions: Our findings indicated that RBM3 was required for efficient inflammatory carcinogenesis in the murine CAC model and suggested that RBM3 could be a predictive biomarker of CAC risk and a new therapeutic target for cancer prevention in patients with IBD.