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

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/en...

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Published in:Hepatology (Baltimore, Md.) Md.), 2014-01, Vol.59 (1), p.216-227
Main Authors: Reebye, Vikash, Sætrom, Pål, Mintz, Paul J., Huang, Kai‐Wen, Swiderski, Piotr, Peng, Ling, Liu, Cheng, Liu, Xiaoxuan, Lindkær‐Jensen, Steen, Zacharoulis, Dimitris, Kostomitsopoulos, Nikolaos, Kasahara, Noriyuki, Nicholls, Joanna P., Jiao, Long R., Pai, Madhava, Spalding, Duncan R., Mizandari, Malkhaz, Chikovani, Tinatin, Emara, Mohamed M., Haoudi, Abdelali, Tomalia, Donald A., Rossi, John J., Habib, Nagy A.
Format: Article
Language:English
Subjects:
Albumins - metabolism
Animals
Carcinoma, Hepatocellular - complications
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - pathology
CCAAT-Enhancer-Binding Protein-alpha - metabolism
Chemical Sciences
Drug Evaluation, Preclinical
Gene expression
Gene Expression Regulation
Genetic Therapy
Hep G2 Cells
Hepatology
Humans
Injections, Intravenous
Liver - pathology
Liver cancer
Liver cirrhosis
Liver Cirrhosis - complications
Liver Function Tests
Liver Neoplasms, Experimental - complications
Liver Neoplasms, Experimental - drug therapy
Liver Neoplasms, Experimental - pathology
Male
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins c-myc - metabolism
Rats
Rats, Wistar
Receptors, Interleukin-6 - metabolism
RNA - therapeutic use
STAT3 Transcription Factor - metabolism
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Summary: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. (Hepatology 2014;58:216–227)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.26669