A Novel RNA Oligonucleotide Improves Liver Function and Inhibits Liver Carcinogenesis in vivo
Conference Recording Nov 17, 2013
About the Speaker
Professor Nagy Habib is Lead Clinician for the HPB Unit at Imperial College Healthcare NHS Trust and Head of the Department of HPB Surgery at Imperial College London. In June 2007 he was also appointed Pro Rector for Commercial Affairs at the university. Professor Habib is a translational researcher who pioneered the first clinical trial in the use of adenovirus and plasmid for the treatment of liver cancer, as well as the use of plasmid gene therapy in hydrodynamic gene delivery.
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-a (C/EBPa). Increased levels of both C/EBPa and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation were observed in saRNA transfected human (HepG2) HCC cell lines.
Intravenous injection of C/EBPa-saRNA in a liver cirrhotic rat model with multifocal liver tumours caused a significant increase in circulating serum albumin levels and amelioration of liver function. Concomitantly, after three injections over seven days, the tumour burden decreased by 80% (p = 0.003) with a 40% reduction in a marker pre-neoplastic transformation.
Using mRNA expression microarray in C/EBPa-saRNA transfected HepG2 cells, we found down-regulation of genes strongly enriched for negative regulation of apoptosis, angiogenesis and metastasis. Up-regulated genes were enriched for tumour suppressors and positive regulators of cell differentiation. Furthermore, quantitative PCR and Western-blot analysis of C/EBPa-saRNA transfected cells suggested an anti-proliferative effect via suppression of IL6R, c-Myc and reduced 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.