Abstract 5515: Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2

Abstract

Abstract Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA (miRNA) biogenesis. However, the role of Dicer and its downstream miRNAs in colorectal cancer (CRC) remain largely unclear. Here, we found that Dicer was downregulated in tumour samples of CRC patients at both mRNA and protein levels. Importantly, more tumours were developed in mice with intestinal epithelial cells specific deletion of Dicer (Dicerloxp/+&VillinCre mice) after azoxymethane (AOM) and dextran sulfate sodium (DSS) administration. Interestingly, deletion of Dicer in intestinal epithelial cells led to severe chronic inflammation and cytoskeleton remodeling of intestinal epithelium layer in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines (RKO-WT/RKO-DICER-/-, HCT116-WT/ HCT116-DICER-/- and DLD-WT/DLD-DICER-/-) showed that miR-324-5p was one of the most significant decreased miRNAs. In the intestinal epithelium of Dicerloxp/loxp&VillinCre mice, miR-324-5p was also found to be markedly downregulated. Mechanistically, miR-324-5p directly bound to the 3'untranslated regions (3'UTRs) of HMGXB3 and WASF-2, two key proteins participated in cytoskeleton remodeling, to suppress their expression. Intraperitoneal injection of miR-324-5p AgomiR curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in Dicerloxp/+&VillinCre mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in cytoskeleton remodeling and maintaining integrity of intestinal barriers and as such alludes to the possibility of screening for small-molecule compounds that boost Dicer activity as a potential strategy in the treatment of colorectal cancer. Citation Format: Lina Sun, Jianming Li. Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5515. doi:10.1158/1538-7445.AM2017-5515