Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1alpha expression in tumor cells and hepatocytes

Gene Ther. 2008 Apr;15(8):572-82. doi: 10.1038/sj.gt.3303103. Epub 2008 Feb 14.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a ubiquitously expressed oxygen-regulated transcription factor composed of alpha and beta subunits. HIF-1 activates transcription of various genes including those involved in metastatic tumor growth. In the present study, HIF-1alpha expression in tumor-bearing mouse liver was examined after inoculation of tumor cells into portal vein. We found that tumor-bearing liver showed greatly increased HIF-1alpha expression. Plasmid DNA (pDNA) expressing short hairpin RNA targeting HIF-1alpha (pshHIF-1alpha) was effective in suppressing protein expression of HIF-1alpha in vitro. Intravenous injection of pshHIF-1alpha by hydrodynamics-based procedure reduced the HIF-1alpha protein expression in both normal and tumor cells and tumor cell number in the liver. Pre-injection of pshHIF-1alpha to mice, by which pDNA was delivered only to liver cells, not to tumor cells, was also effective in reducing the number of tumor cells inoculated 3 days after pDNA injection. These findings indicate that HIF-1alpha expression is increased in normal liver cells as well as tumor cells, and HIF-1alpha expression plays an important role in tumor progression. Use of the RNA interference (RNAi) of HIF-1 is an effective strategy for inhibiting tumor cell growth, and both tumor and normal cells can be the target for RNAi-based anticancer treatment.Gene Therapy (2008) 15, 572-582; doi:10.1038/sj.gt.3303103; published online 14 February 2008.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay / methods
  • Gene Expression
  • Genetic Therapy / methods*
  • Hepatocytes / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / analysis
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary*
  • Liver Neoplasms / therapy*
  • Male
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 9 / analysis
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Plasmids
  • RNA Interference*
  • RNA, Small Interfering / administration & dosage*
  • Transfection / methods

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9