https://scholars.lib.ntu.edu.tw/handle/123456789/503637
標題: | Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo | 作者: | Reebye V. S?trom P. Mintz P.J. KAI-WEN HUANG Swiderski P. Peng L. Liu C. Liu X. Lindk?r-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. Haoudi A. Tomalia D.A. Rossi J.J. Habib N.A. |
公開日期: | 2014 | 出版社: | John Wiley and Sons Inc. | 卷: | 59 | 期: | 1 | 起(迄)頁: | 216-227 | 來源出版物: | Hepatology | 摘要: | 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. ? 2013 by the American Association for the Study of Liver Diseases. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84894856234&doi=10.1002%2fhep.26669&partnerID=40&md5=d6eb393b8d70047e8fdf262c56f12441 https://scholars.lib.ntu.edu.tw/handle/123456789/503637 |
ISSN: | 0270-9139 | DOI: | 10.1002/hep.26669 | SDG/關鍵字: | 4 hydroxyphenylpyruvic acid dioxygenase; alanine aminotransferase; albumin; aspartate aminotransferase; bilirubin; CCAAT enhancer binding protein alpha; cyclin D1; cyclin dependent kinase inhibitor 1A; dioxygenase; glutathione transferase P1; growth arrest and DNA damage inducible protein 45; growth arrest and DNA damage inducible protein 45 beta; hepatocyte nuclear factor 1alpha; hepatocyte nuclear factor 4alpha; interleukin 6 receptor; messenger RNA; oligonucleotide; plasminogen; protein mcl 1; retinoblastoma protein; RNA; scatter factor; short activating RNA oligonucleotide; Smad7 protein; STAT3 protein; suppressor of cytokine signaling 3; survivin; transcription factor RUNX3; transforming growth factor beta1; unclassified drug; X linked inhibitor of apoptosis; albuminoid; CCAAT enhancer binding protein alpha; IL6R protein, human; interleukin 6 receptor; Myc protein; MYC protein, human; RNA; STAT3 protein; STAT3 protein, human; CCAAT enhancer binding protein alpha; RNA; albumin blood level; angiogenesis; animal experiment; animal model; animal tissue; antiproliferative activity; apoptosis; Article; cancer inhibition; cell proliferation; controlled study; down regulation; gene expression; gene targeting; genetic transfection; HepG2 cell line; human; human cell; in vivo study; liver carcinogenesis; liver cell carcinoma; liver cirrhosis; liver function; liver tumor; male; metastasis; microarray analysis; nonhuman; oligonucleotide therapy; oncogene c myc; polymerase chain reaction; priority journal; quantitative analysis; rat; rat model; tumor suppressor gene; tumor volume; upregulation; Western blotting; animal; article; cell strain HepG2; DNA microarray; drug screening; experimental liver neoplasm; gene expression regulation; gene therapy; intravenous drug administration; liver; liver cell carcinoma; liver cirrhosis; liver function test; metabolism; pathology; Wistar rat; Carcinoma, Hepatocellular; complication; Liver Neoplasms, Experimental; Albumins; Animals; Carcinoma, Hepatocellular; CCAAT-Enhancer-Binding Protein-alpha; Drug Evaluation, Preclinical; Gene Expression Regulation; Genetic Therapy; Hep G2 Cells; Humans; Injections, Intravenous; Liver; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms, Experimental; Male; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Receptors, Interleukin-6; RNA; STAT3 Transcription Factor; Albumins; Animals; Carcinoma, Hepatocellular; CCAAT-Enhancer-Binding Protein-alpha; Drug Evaluation, Preclinical; Gene Expression Regulation; Genetic Therapy; Hep G2 Cells; Humans; Injections, Intravenous; Liver; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms, Experimental; Male; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Receptors, Interleukin-6; RNA; STAT3 Transcription Factor |
顯示於: | 醫學系 |
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