Abstract LB-306: A novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo.

Abstract

Abstract Hepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Therapies to simultaneously reduce tumour burden and improve liver function are limited. Here, we show an innovative RNA-based targeted approach to enhance endogenous albumin production whilst reducing liver tumour burden. We designed short activating RNA (saRNA) oligonucleotides to enhance expression of the transcriptional regulator and activator of albumin gene expression, CCAAT/enhancer-binding protein-α (C/EBPα). Increased levels of both C/EBPα and albumin mRNA in addition to a 3-fold increase in albumin secretion and a 50% decrease in cell proliferation were observed in saRNA transfected hepatocellular carcinoma cells (HepG2). Intravenous injection of C/EPBα-saRNA in a liver cirrhotic rat model with multifocal liver tumours caused a significant increase in circulating serum albumin levels, and reduction in circulating ALT and AST levels- suggesting an amelioration of liver function. Concomitantly a significant reduction in tumour burden and pre-neoplastic transformation placental glutathione S-transferase (GST-p) staining was observed. Using mRNA expression microarray, quantitative PCR, Western blot and methylation analysis of CpG islands in C/EPBα-saRNA transfected HepG2 cells, we found up-regulation of C/EBPα and albumin; and a negative regulation of IL6R, c-Myc and STAT3 phosphorylation. We demonstrate for the first time that a novel injectable saRNA oligonucleotide successfully reduces tumour burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model. Citation Format: Vikash Reebye. A novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-306. doi:10.1158/1538-7445.AM2013-LB-306 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.