Korean J Hepatol.  2010 Sep;16(3):280-287. 10.3350/kjhep.2010.16.3.280.

Effects of the knockdown of hypoxia inducible factor-1alpha expression by adenovirus-mediated shRNA on angiogenesis and tumor growth in hepatocellular carcinoma cell lines

Affiliations
  • 1Brain Korea 21 project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  • 2Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. drpjy@yuhs.ac
  • 3Liver Cirrhosis Clinical Research Center, Yonsei University College of Medicine, Seoul, Korea.
  • 4Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND/AIMS
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a central transcriptional factor involved in the cellular responses related to various aspects of cancer biology, including proliferation, survival, and angiogenesis, and the metabolism of the extracellular matrix in hypoxia. This study evaluated whether adenovirus-mediated small hairpin RNA (shRNA) against HIF-1alpha (shHIF-1alpha) inhibits cell proliferation and angiogenesis in hepatocellular carcinoma (HCC) cell lines.
METHODS
Knockdown of HIF-1alpha expression was constructed by adenovirus-mediated RNA interference tools, and HCC cell lines infected with shHIF-1alpha coding virus were cultured under a hypoxia condition (1% O2) for 24 hours. Following infection, the expression levels of HIF-1alpha, angiogenesis factors, and matrix metalloproteinase (MMP) were examined using Western blotting. Cell proliferation and angiogenesis were measured by a cell proliferation assay (MTT assay) and an angiogenesis-related assay (invasion and tube-formation assay), respectively.
RESULTS
Adenovirus mediated inhibition of HIF-1alpha induced suppression of tumor growth in HCC cell lines. It also down-regulated the expression of angiogenesis factor and MMP proteins. Angiogenesis as well as mobility of vascular cells to tumor was suppressed by adenovirus-mediated shHIF-1alpha-infected groups in human umbilical vein endothelial cells (HUVECs).
CONCLUSIONS
These data suggest that adenovirus-mediated inhibition of HIF-1alpha inhibits the invasion, tube formation, and cell growth in HUVECs and HCC cells.

Keyword

Angiogenesis; Hypoxia-inducible factor-1alpha (HIF-1alpha); Small hairpin RNA (shRNA); Human umbilical vein endothelial cells (HUVECs); Hepatocellular carcinoma

MeSH Terms

Adenoviridae/genetics
Carcinoma, Hepatocellular/*blood supply/metabolism/therapy
Cell Line, Tumor
Cell Proliferation
Endothelial Cells/metabolism
Gene Knockdown Techniques
Genetic Vectors
Humans
Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists &
Liver Neoplasms/*blood supply/metabolism/therapy
Matrix Metalloproteinases/metabolism
Neovascularization, Pathologic/genetics/metabolism/*therapy
RNA Interference
RNA, Small Interfering/metabolism
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