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Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway

Oncogene volume 25, pages 7009–7018 (2006)Cite this article

Abstract

This study is to investigate the molecular mechanism of radiation-enhanced cell invasiveness of hepatocellular carcinoma (HCC) correlating with clinical patients undergoing radiotherapy and subsequently developing metastasis. Three HCC cell lines (HepG2, Hep3B and Huh7) and normal hepatocyte cell line (CL-48) were irradiated with different doses. The effect of radiation on cell invasiveness was determined using the Boyden chamber assay. Radiation-enhanced invasion capability was evident in HCC cells but not in normal hepatocytes. Invasion was observed in gelatin-coated but not fibronectin-coated or type I collagen-coated membranes. Radiation upregulated matrix metalloproteinase-9 (MMP-9) mRNA level, MMP-9 protein level and MMP-9 activity. MMP-9 antisense oligonucleotides inhibited radiation-induced MMP-9 expression and thereby significantly inhibited radiation-induced HCC invasion. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt chemical inhibitors LY294002 and wortmannin suppressed radiation-induced MMP-9 mRNA expression. Transient transfection with dominant-negative Akt plasmid also showed that the PI3K/Akt-signaling pathway was involved in this radiation-induced MMP-9 expression. Moreover, nuclear factor-κB (NF-κB) decoy oligodeoxynucleotide suppressed radiation enhanced MMP-9 promoter activity completely. PI3K/Akt chemical inhibitors inhibited radiation-induced NF-κB-driven luciferase promoter activity. Taken together, our results indicated that sublethal dose of radiation could enhance HCC cell invasiveness by MMP-9 expression through the PI3K/Akt/NF-κB signal transduction pathway.

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Acknowledgements

This work was supported by the National Science Council, Execute Yuan, Taiwan, ROC (Grant number: NSC93-2323-B-002-009 & NSC94-2323-B-002-012), the Department of Health (Grant number: CCMP94-RD-016), and the research grants NTUH 94N25 and NTUH 95N04 National Taiwan University Hospital.

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Authors and Affiliations

  1. Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan

    J C-H Cheng, C H Chou & C-Y Hsieh

  2. Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan

    M L Kuo

  3. Department of Obstetrics and Gynecology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan

    C-Y Hsieh

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  1. J C-H Cheng
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Correspondence to C-Y Hsieh.

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Cheng, JH., Chou, C., Kuo, M. et al. Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway. Oncogene 25, 7009–7018 (2006). https://doi.org/10.1038/sj.onc.1209706

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