Silencing hypoxia-inducible factor-1α inhibits cell migration and invasion under hypoxic environment in malignant gliomas

  • Authors:
    • Satoshi Fujiwara
    • Kou Nakagawa
    • Hironobu Harada
    • Shigeyuki Nagato
    • Koji Furukawa
    • Mikio Teraoka
    • Toshimoto Seno
    • Keizo Oka
    • Shinji Iwata
    • Takanori Ohnishi
  • View Affiliations

  • Published online on: April 1, 2007     https://doi.org/10.3892/ijo.30.4.793
  • Pages: 793-802
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Abstract

alignant gliomas are characterized by active invasiveness, necrosis, and vascular proliferation. These pathological features have been speculated to be caused by tissue hypoxia. Hypoxia-inducible factor-1 (HIF-1), which is controlled by rapid stabilization of the HIF-1α subunit, is a pivotal transcriptional factor in the cellular response to hypoxia. Although many studies have described the relationship between tumor angiogenesis and hypoxic environment, the roles of HIF-1 in cell invasion have been barely elucidated in malignant gliomas. We investigated the role of HIF-1α in the motile and invasive activities of human glioma cells under hypoxia. Four malignant glioma cell lines, U87MG, U251MG, U373MG, and LN18, were cultured under 21 and 1% oxygen concentration. Expression of HIF-1α under hypoxia was observed to be much higher than that under normoxia in all cell lines. Introducing HIF-1α-targeted small interfering RNA (HIF-1α siRNA) into the glioma cell lines resulted in downregulation of HIF-1α expression, and significantly suppressed glioma cell migration in vitro. Furthermore, invasiveness was significantly reduced in the cells transfected with HIF-1α siRNA compared with those transfected with the control siRNA. Co-culture of glioma spheroids and rat brain slices showed that HIF-1α siRNA-transfected glioma cells failed to invade the surrounding normal brain tissue in an organotypic brain slice model. These effects of HIF-1α siRNA were more conspicuous under hypoxia than under normoxia. In addition, under hypoxic conditions, the level of matrix metalloproteinase (MMP)-2 mRNA was upregulated, and that of tissue inhibitor of metalloproteinase (TIMP)-2 was downregulated in all glioma cell lines. Treatment with HIF-1α siRNA resulted in downregulation of MMP-2 mRNA and upregulation of TIMP-2 mRNA. Furthermore, the enzyme activities of MMP-2 and MMP-9, both of which were activated by hypoxia, decreased with the introduction of HIF-1α siRNA. These findings suggest that overexpression of HIF-1α induced by hypoxic stress is an essential event in the activation of glioma cell motility through alteration of invasion-related molecules. Targeting the HIF-1α molecule may be a novel therapeutic strategy for malignant gliomas.

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April 2007
Volume 30 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Fujiwara S, Nakagawa K, Harada H, Nagato S, Furukawa K, Teraoka M, Seno T, Oka K, Iwata S, Ohnishi T, Ohnishi T, et al: Silencing hypoxia-inducible factor-1α inhibits cell migration and invasion under hypoxic environment in malignant gliomas. Int J Oncol 30: 793-802, 2007
APA
Fujiwara, S., Nakagawa, K., Harada, H., Nagato, S., Furukawa, K., Teraoka, M. ... Ohnishi, T. (2007). Silencing hypoxia-inducible factor-1α inhibits cell migration and invasion under hypoxic environment in malignant gliomas. International Journal of Oncology, 30, 793-802. https://doi.org/10.3892/ijo.30.4.793
MLA
Fujiwara, S., Nakagawa, K., Harada, H., Nagato, S., Furukawa, K., Teraoka, M., Seno, T., Oka, K., Iwata, S., Ohnishi, T."Silencing hypoxia-inducible factor-1α inhibits cell migration and invasion under hypoxic environment in malignant gliomas". International Journal of Oncology 30.4 (2007): 793-802.
Chicago
Fujiwara, S., Nakagawa, K., Harada, H., Nagato, S., Furukawa, K., Teraoka, M., Seno, T., Oka, K., Iwata, S., Ohnishi, T."Silencing hypoxia-inducible factor-1α inhibits cell migration and invasion under hypoxic environment in malignant gliomas". International Journal of Oncology 30, no. 4 (2007): 793-802. https://doi.org/10.3892/ijo.30.4.793