A regulatory program that promotes metastasis in colorectal cancer (CRC) through modulation of mRNA stability.

Abstract

3523 Background: CRC progression accompanies dysregulations in pathways of gene expression control. Regulatory pathways that govern RNA decay have emerged as key mechanisms coopted by cancer cells. Here, we have described a novel regulatory program that acts as a suppressor of metastasis in CRC. Methods: We have developed a computational approach called PRADA that identifies master regulators of aberrant mRNA stability. By applying this tool to a compendium of gene expression data collected from patient samples and colon cancer cell lines, we have identified a novel regulatory program involved in CRC metastasis. We have used xenograft models and genomic technologies to functionally dissect this pathway. We have also performed multivariate analysis in public datasets, as well as qPCR-based measurements in tumor samples to establish its clinical relevance. Results: PRADA identified the RNA-binding protein RBMS1 as a key factor in CRC metastasis. RBMS1, which is silenced in highly metastatic cells, binds and stabilizes a large regulon of mRNAs. Silencing RBMS1 in established lines resulted in increased liver colonization in xenograft models and its over-expression reduced metastasis. We also identified the set of genes that are directly bound and regulated by RBMS1 and function downstream. Loss of RBMS1 and its regulon provide a signature predictive of RFS in localized CRC (n = 574, HR = 0.48, p = 0.038) even when controlled for known prognostic factors in a multivariate analysis (Table). We also observed a 4-fold reduction (P<1e-3) in the expression of RBMS1 in stage IV tumors relative to earlier stage disease. Conclusions: In sum, we have discovered a previously unknown regulatory pathway of RNA stability that acts as a suppressor of metastasis in CRC which may inform new therapeutic targets among the RBMS1 regulon for adjuvant therapy.[Table: see text]