Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo

Vikash Reebye, Pål Sætrom, Paul J. Mintz, Kai Wen Huang, Piotr Swiderski, Ling Peng, Cheng Liu, Xiaoxuan Liu, Steen Lindkær-Jensen, Dimitris Zacharoulis, Nikolaos Kostomitsopoulos, Noriyuki Kasahara, Joanna P. Nicholls, Long R. Jiao, Madhava Pai, Duncan R. Spalding, Malkhaz Mizandari, Tinatin Chikovani, Mohamed M. Emara, Abdelali HaoudiDonald A. Tomalia, John J. Rossi, Nagy A. Habib

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Hepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Here we show an innovative RNA-based targeted approach to enhance endogenous albumin production while reducing liver tumor burden. We designed short-activating RNAs (saRNA) to enhance expression of C/EBPα (CCAAT/enhancer-binding protein-α), a transcriptional regulator and activator of albumin gene expression. Increased levels of both C/EBPα and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation was observed in C/EBPα-saRNA transfected HepG2 cells. Intravenous injection of C/EBPα-saRNA in a cirrhotic rat model with multifocal liver tumors increased circulating serum albumin by over 30%, showing evidence of improved liver function. Tumor burden decreased by 80% (P = 0.003) with a 40% reduction in a marker of preneoplastic transformation. Since C/EBPα has known antiproliferative activities by way of retinoblastoma, p21, and cyclins, we used messenger RNA (mRNA) expression liver cancer-specific microarray in C/EBPα-saRNA-transfected HepG2 cells to confirm down-regulation of genes strongly enriched for negative regulation of apoptosis, angiogenesis, and metastasis. Up-regulated genes were enriched for tumor suppressors and positive regulators of cell differentiation. A quantitative polymerase chain reaction (PCR) and western blot analysis of C/EBPα-saRNA-transfected cells suggested that in addition to the known antiproliferative targets of C/EBPα, we also observed suppression of interleukin (IL)6R, c-Myc, and reduced STAT3 phosphorylation. Conclusion: A novel injectable saRNA-oligonucleotide that enhances C/EBPα expression successfully reduces tumor burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model.

Original languageEnglish (US)
Pages (from-to)216-227
Number of pages12
JournalHepatology
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo'. Together they form a unique fingerprint.

  • Cite this

    Reebye, V., Sætrom, P., Mintz, P. J., Huang, K. W., Swiderski, P., Peng, L., Liu, C., Liu, X., Lindkær-Jensen, S., Zacharoulis, D., Kostomitsopoulos, N., Kasahara, N., Nicholls, J. P., Jiao, L. R., Pai, M., Spalding, D. R., Mizandari, M., Chikovani, T., Emara, M. M., ... Habib, N. A. (2014). Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo. Hepatology, 59(1), 216-227. https://doi.org/10.1002/hep.26669