Stromal Loss of mRNA‐Binding Protein IMP1 promotes a Pro‐Tumorigenic Colon Tumor Microenvironment in vivo

Abstract

BackgroundInsulin‐like growth factor II mRNA‐binding protein 1 (IMP1) is an oncofetal protein that modulates mRNA stabilization, localization, and translation. Recent studies suggest that IMP1 may play a role in colonic mesenchymal stem cells during wound healing. We have demonstrated an oncogenic role for IMP1 in colorectal cancer (CRC) cells; however, it is not known how non‐epithelial IMP1 contributes to CRC in vivo.Methods: Using the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis‐associated CRC, we evaluated tumorigenesis in mice with mesenchymal‐specific Imp1loss (Dermo1Cre;Imp1floxed mice;Imp1ΔMes). Furthermore, isolated mesenchyme from tumor‐bearing mice was evaluated for changes in growth factors and cytokines via antibody array.Results: We demonstrate that Imp1 ΔMesmice treated with AOM/DSS exhibit a significant increase in tumor number, size, and load compared to controls. Isolated mesenchmye from AOM/DSS‐ treated Imp1 ΔMes mice show, among other things, a significant increase in hepatocyte growth factor (HGF) expression, suggesting that IMP1 loss favors a pro‐tumorigenic environment, potentially via up‐regulation of the HGF pathway.ConclusionsOur results thus far indicate a novel, protective role for stromal IMP1 in colon tumorigenesis, likely via negative regulation of HGF signaling in the setting of colitis‐associated CRC. Future studies will determine the direct mechanisms for IMP1 regulation of the HGF pathway and may define a previously unknown, therapeutically tractable mechanism of stromal:epithelial crosstalk in CRC.Funding : NIH RO1 DK056645 (AKR), NIH K01 DK100485 (KEH) HHMI Medical Fellowship (ETL), NIH UO1 DK085551 (NIDDK/NIAID Intestinal Stem Cell Consortium)