MicroRNA-regulated non-viral vectors with improved tumor specificity in an orthotopic rat model of hepatocellular carcinoma

J. A. Ronald, R. Katzenberg, C. H. Nielsen, H. J. Jae, L. V. Hofmann, S. S. Gambhir

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

In hepatocellular carcinoma (HCC), tumor specificity of gene therapy is of utmost importance to preserve liver function. MicroRNAs (miRNAs) are powerful negative regulators of gene expression and many are downregulated in human HCC. We identified seven miRNAs that are also downregulated in tumors in a rat hepatoma model (P<0.05) and attempted to improve tumor specificity by constructing a panel of luciferase-expressing vectors containing binding sites for these miRNAs. Attenuation of luciferase expression by the corresponding miRNAs was confirmed across various cell lines and in mouse liver. We then tested our vectors in tumor-bearing rats and identified two miRNAs, miR-26a and miR-122, that significantly decreased expression in liver compared with the control vector (6.40 and 0.26%, respectively; P<0.05). In tumor, miR-122 had a nonsignificant trend towards decreased (∼50%) expression, whereas miR-26 had no significant effect on tumor expression. To our knowledge, this is the first work using differentially expressed miRNAs to de-target transgene expression in an orthotopic hepatoma model and to identify miR-26a, in addition to miR-122, for de-targeting liver. Considering the heterogeneity of miRNA expression in human HCC, this information will be important in guiding development of more personalized vectors for the treatment of this devastating disease.

Original languageEnglish (US)
Pages (from-to)1006-1013
Number of pages8
JournalGene Therapy
Volume20
Issue number10
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • bioluminescence
  • hepatocellular carcinoma
  • microRNA
  • rat model

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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