title: Overexpression of von Hippel-Lindau protein synergizes with doxorubicin to suppress hepatocellular carcinoma in mice.
abstract: OBJECTIVE
  Hypoxia-inducible factors (HIFs) and nuclear factor-κB (NF-κB) regulate genes involved in carcinogenesis and progression of cancers including hepatocellular carcinoma (HCC). The von Hippel-Lindau (VHL) protein (pVHL) targets HIFα subunits for destruction and participates in modulating the activity of NF-κB. The present study aimed to investigate whether the overexpression of pVHL synergizes with doxorubicin in the treatment of HCC.
  
  
  METHODS
  Overexpression of pVHL was induced by infecting mouse HCC Hepa1-6 and H22 cells, or injecting subcutaneous Hepa1-6 tumors in C57BL/c mice, with adenoviral vectors encoding mouse VHL gene. Cell proliferation, apoptosis, tumoral angiogenesis, and gene expression and DNA-binding activity of NF-κB were examined. The therapeutic effects of pVHL were also evaluated in orthotopic Hepa1-6 tumors by intraportal delivery of Ad-VHL.
  
  
  RESULTS
  Ad-VHL enhanced the anti-tumor activity of doxorubicin by inhibiting cell proliferation, and causing cell cycle arrest and apoptosis. The Ad-VHL infection downregulated HIF-1α and HIF-2α expression, and inhibited NF-κB activity and the expression of genes involved in apoptosis, proliferation, angiogenesis, invasion, and metastasis. Injection of Ad-VHL into HCC tumors augmented doxorubicin-induced suppression of tumor growth by inhibiting cell proliferation and tumor angiogenesis, and by inducing cell apoptosis. Effects on the expression of HIFαs, activity of NF-κB, and their downstream genes were in accordance with the in vitro findings. Intraportal injection of Ad-VHL enhanced the efficacy of doxorubicin to suppress the growth of orthotopic liver tumors.
  
  
  CONCLUSIONS
  By targeting HIF and NF-κB, overexpression of pVHL enhances the efficacy of doxorubicin, and warrants consideration as a potential therapeutic strategy for treating HCC.
authors.affiliation: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Jizhou
authors.initials: J
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Zhu
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
authors.forename: Bei
authors.initials: B
authors.lastname: Sun
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage*; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011994:Recombinant Proteins / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D004317:Doxorubicin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011994:Recombinant Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse