RRC ID 73365
Author Miyoshi A, Kitajima Y, Ide T, Ohtaka K, Nagasawa H, Uto Y, Hori H, Miyazaki K.
Title Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-1alpha-independent manner.
Journal Int J Oncol
Abstract Tumor hypoxia has been reported to induce tumor progression in several carcinomas. Current studies have shown that hypoxia inducible factor-1alpha (HIF-1alpha) is stabilized under hypoxic conditions and transactivates various genes related to cancer aggressiveness. In the present study, we examined whether hypoxia affects cancer invasion in hepatocellular carcinoma. We aimed to solve the molecular mechanism of tumor invasion under the hypoxic condition. We showed that tumor hypoxia accelerated cancer invasion in two hepatoma cell lines. Using Western blot and RT-PCR analyses we demonstrated striking evidence that the expression of HIF-1alpha, ETS-1, MMP-7 and MT1-MMP was strongly upregulated by hypoxic stimulation. To examine whether these invasion-related genes are regulated by HIF-1alpha, we treated hepatoma cells with TX-402, which was reported to repress HIF-1alpha expression. HIF-1alpha expression was strongly repressed by the TX-402 treatment. In contrast, the expression of ETS-1, MMP-7 and MT1-MMP mRNA was not affected by TX-402 treatment. We further established stable transfectants in which HIF-1alpha dominant negative vector was introduced into Hep3B cells (pHIF-1alphaDN). In the pHIF-1alphaDN cells, the expression of ETS-1, MMP-7 and MT1-MMP was not repressed. Moreover, the invasion activity of pHIF-1alphaDN was not altered, compared with that of the mock. In hepatoma cells, we provided evidence that hypoxic stress accelerates cancer invasion by upregulating ETS-1 and the MMP family by an HIF-1alpha-independent pathway.
Volume 29(6)
Pages 1533-9
Published 2006-12-1
DOI 10.3892/ijo.29.6.1533
PMID 17088993
MeSH Carcinoma, Hepatocellular / enzymology Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Cell Growth Processes / physiology Cell Hypoxia / physiology Cell Movement / physiology Cyclic N-Oxides / pharmacology Gene Expression Regulation, Neoplastic / drug effects Gene Expression Regulation, Neoplastic / physiology Humans Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Liver Neoplasms / enzymology Liver Neoplasms / genetics Liver Neoplasms / metabolism* Liver Neoplasms / pathology Matrix Metalloproteinases / biosynthesis* Matrix Metalloproteinases / genetics Neoplasm Invasiveness Proto-Oncogene Protein c-ets-1 / genetics Quinoxalines / pharmacology Reverse Transcriptase Polymerase Chain Reaction / methods Transfection Up-Regulation
IF 3.899
Human and Animal Cells Hep G2