Abstract 169: Metastatic colorectal cancer associated long non-coding RNAs identified by transcriptome sequencing of matched primary and metastatic patient tissues

Abstract

Abstract Colorectal Cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. Approximately 50% of patients with CRC develops metastatic disease (mCRC) with a 5-year survival of less than 20%. To date, colorectal cancer research has primarily focused on the deregulation of protein-coding genes, however due to recent technological advances we can now focus on the under-studied and emerging class of long non-coding RNAs (lncRNAs). Despite advances in our understanding of primary CRC oncogenesis, the mechanisms driving the progression from primary to metastatic colorectal cancer remain poorly characterized. To address this, we performed ab initio transcriptome assembly to detect aberrant transcripts comparing matched normal, primary, and metastatic colon cancer tissues from a cohort of patients. This led us to discover 56 novel lncRNAs solely altered in metastasis when compared to normal and primary tissues, which we refer to as metastatic colorectal cancer associated long non-coding RNAs (mCCAL). To demonstrate functional significance, we characterized the most up-regulated novel lncRNA, mCCAL1. mCCAL1 was highly expressed in multiple colon cancer cell lines with the highest expression in HCT-116 and Lovo cell lines. Silencing mCCAL1's expression caused a decrease in cellular migration in HCT-116 cells and invasion in Lovo cells relative to controls. Furthermore, gene set enrichment analysis of our microarray results and patient cohort data revealed differentially regulated genes enriched in epithelial to mesenchymal transition (EMT), chromatin remodeling, methyltransferase activity, and target genes of the Polycomb Repressive Complex 2 (PRC2). Modulating expression of mCCAL1 also decreased expression of H3K27me3 supporting its role in chromatin remodeling. All together, this is the first study to compare matched patient tissues to discover metastatic lncRNAs in colorectal cancer. Our data revealed that mCCAL1 promotes cellular migration and invasion, EMT, and may function through its association with PRC2. Moving forward, we intend to further understand how mCCALs contribute to metastatic progression of colorectal cancer with the intent of revealing novel cancer diagnostics and therapies. Citation Format: Jessica M. Silva-Fisher, Ha Dang, Julie Grossman, Nicole White, Christopher Cabanski, Simon Goedegebuure, Timothy Fleming, Elizabeth Pittman, Robert Fulton, Matthew Strand, Albert C. Lockhart, Timothy Ley, Richard Wilson, Ryan Fields, Christopher Maher. Metastatic colorectal cancer associated long non-coding RNAs identified by transcriptome sequencing of matched primary and metastatic patient tissues. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 169. doi:10.1158/1538-7445.AM2015-169