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Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo
- 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
- et al.
Published Web Location
https://doi.org/10.1002/hep.26669Abstract
Unlabelled
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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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