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

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/EBP? (CCAAT/enhancer-binding protein-?), a transcriptional regulator and activator of albumin gene expression. Increased levels of both C/EBP? and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation was observed in C/EBP?-saRNA transfected HepG2 cells. Intravenous injection of C/EBP?-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/EBP? has known antiproliferative activities by way of retinoblastoma, p21, and cyclins, we used messenger RNA (mRNA) expression liver cancer-specific microarray in C/EBP?-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/EBP?-saRNA-transfected cells suggested that in addition to the known antiproliferative targets of C/EBP?, we also observed suppression of interleukin (IL)6R, c-Myc, and reduced STAT3 phosphorylation.A novel injectable saRNA-oligonucleotide that enhances C/EBP? expression successfully reduces tumor burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model.

SUBMITTER: Reebye V

PROVIDER: S-EPMC4655108 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Reebye Vikash V Sætrom Pål P Mintz Paul J PJ Huang Kai-Wen KW Swiderski Piotr P Peng Ling L Liu Cheng C Liu Xiaoxuan X Lindkaer-Jensen Steen S Zacharoulis Dimitris D Kostomitsopoulos Nikolaos N Kasahara Noriyuki N Nicholls Joanna P JP Jiao Long R LR Pai Madhava M Spalding Duncan R DR Mizandari Malkhaz M Chikovani Tinatin T Emara Mohamed M MM Haoudi Abdelali A Tomalia Donald A DA Rossi John J JJ Habib Nagy A NA

Hepatology (Baltimore, Md.) 20131209 1

<h4>Unlabelled</h4>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 ...[more]

PMID: 23929703

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Project description:Alcohol liver disease (ALD) is a major cause of liver-related mortality globally, yet there remains an unmet demand for approved ALD drugs. The pathogenesis of ALD involves perturbations to the intestinal barrier and subsequent translocation of bacterial endotoxin that, acting through toll-like receptor 4 (TLR4), promotes hepatic inflammation and progression of ALD. In the present study we investigated the ability of fenretinide (Fen) [N-(4-hydroxyphenyl) retinamide], a synthetic retinoid with known anti-cancer and anti-inflammatory properties, to modulate intestinal permeability and clinical hallmarks of ALD in a mouse model of chronic ethanol (EtOH) exposure. Our results show that EtOH-treated mice had reductions in mRNA and protein expression of intestinal tight junction proteins, including claudin one and occludin, and increases in intestinal permeability and endotoxemia compared to pair-fed mice. Also, EtOH-treated mice had marked increases in hepatic steatosis, liver injury, and expression of pro-inflammatory mediators, including TNF-α, and TLR4-positive macrophages, Kupffer cells, and hepatocytes in the intestines and liver, respectively. In contrast, EtOH + Fen-treated mice were resistant to the effects of EtOH on promoting intestinal permeability and had higher intestinal protein levels of claudin one and occludin. Also, EtOH + Fen-treated mice had significantly lower plasma levels of endotoxin, and reductions in expression of TNF-α and TLR4 positive macrophages, Kupffer cells, and hepatocytes in the intestine and liver. Lastly, we found that EtOH + Fen-treated mice exhibited major reductions in hepatic triglycerides, steatosis, and liver injury compared to EtOH-treated mice. Our findings are the first to demonstrate that Fen possesses anti-ALD properties, potentially through modulation of the intestinal barrier function, endotoxemia, and TLR4-mediated inflammation. These data warrant further pre-clinical investigations of Fen as a potential anti-ALD drug.

Dataset Information

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

Publications

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

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