학술논문
Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo
Document Type
article
Author
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
Source
Hepatology. 59(1)
Subject
Language
Abstract
UnlabelledHepatocellular 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.ConclusionA 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.