Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1alpha expression in tumor cells and hepatocytes.
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.
Takahashi
Y
Y
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Nishikawa
M
M
Takakura
Y
Y
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000628:therapy*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010957:Plasmids; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection / Q000379:methods
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9