Abstract 3960: The role and therapeutic potential of miRNAs in colorectal liver metastasis

Abstract

Abstract Colorectal cancer (CRC) is a leading cause of cancer related deaths worldwide. Liver metastasis occurs in 60% of CRC patients and usually responds poorly to treatment - contributing to mortality rate. MicroRNAs (miRNAs) are highly conserved, endogenously encoded small, non-coding RNA molecules regulating global gene expression. Their role in cancer pathogenesis, including CRC, has been well documented. Detailed miRNA expression analysis on a large cohort of CRC tumors is needed to identify clinically relevant miRNAs and explore their potential to target liver metastases. We analyzed miRNA expression data of 406 CRC tumors from publically available CRC genome sequencing project and identified 58 miRNAs, which were significantly downregulated. Using miRNA target prediction analysis, 10 miRNAs were selected for further studies as they were either known to target genes in cellular pathways associated with CRC liver metastases, or located within a chromosomal loci commonly lost in colorectal liver metastases. qPCR analysis of these 10 selected miRNAs in primary and colorectal liver metastasis tissues and in CRC cell lines demonstrated four miRNAs; miR-132, miR-378f, miR-605, and miR-1976 that are significantly down-regulated with <2 fold change (p>0.05). To investigate the anti-tumorigenic and metastatic properties of miR-132, -378f, -605, and -1976, we transfected 3 different CRC cell lines (SW620, HCT-116, and CT-26) with miR-mimics and subjected them to cell proliferation, apoptosis, soft agar, invasion, and migration assays. Ectopic expression of miR-378f, -605, and -1976 suppressed CRC cell proliferation, anchorage independent growth, migration, and invasion and increased apoptosis. Interestingly, CRC patients with high miR-378f and miR-1976 had better survival compared to low expressing patients (p<0.044). In conclusion, our in vitro findings suggest anti-tumorigenic/metastatic properties of miR-378f, -605, and -1976 in CRC. A further understanding of their function and in vivo therapeutic evaluation may help in developing novel therapeutic strategies for this malignancy. Citation Format: Smiti Snigdha Sahu, Sarah Nabinger, Jiang Guanglong, Allison Bates, Sangbin Lee, Tanaka Hiromi, Yunlong Liu, Janaiah Kota. The role and therapeutic potential of miRNAs in colorectal liver metastasis. [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 3960. doi:10.1158/1538-7445.AM2015-3960