Abstract
Abstract Aberrant activation of the Wnt signaling pathway is causally involved in the formation of most colorectal cancers (CRCs). Whereas detailed knowledge exists regarding Wnt regulated protein coding genes, much less is known about the possible involvement of non-coding RNAs. Here we used TaqMan Array MicroRNA Cards, capable of detecting 664 unique human microRNAs (miRNAs), to describe changes of the miRNA transcriptome following disruption of beta-catenin/TCF4 activity in DLD1 CRC cells. Most miRNAs appeared to respond independently of host gene regulation and proximal TCF4 chromatin occupancy. A module of miRNAs suppressed by Wnt signaling in vitro was downregulated in a series of human primary CRCs (n = 46), and CRC cell lines (n = 7), relative to normal adjacent mucosa (n = 14). Several of these miRNAs (miR-145, miR-126, miR-30e-3p, and miR-139-5p) markedly inhibited CRC cell growth in vitro when ectopically expressed. By using an integrative approach of proteomics and microarrays, together interrogating thousands of proteins and genome-wide mRNA levels, we also provide detailed insight into the target gene network controlled by miR-30e-3p. Specifically HELZ and PIK3C2A were directly repressed via several functional seed matching binding motifs located within the transcripts. siRNA-mediated silencing of PIK3C2A partly phenocopied the growth suppressive phenotype of miR-30e-3p suggesting that miR-30e-3p restricts CRC cell growth in part by targeting PIK3C2A. Collectively, our study demonstrates that multiple miRNAs are upregulated as a consequence of forced attenuation of Wnt signaling in CRC cells, and some of these miRNAs inhibit cell growth, possibly through repression of several growth stimulatory cancer-related genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3964. doi:10.1158/1538-7445.AM2011-3964
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