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Actin-sequestering protein, thymosin beta-4, is a novel hypoxia responsive regulator

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Abstract

Angiogenesis is induced by soluble factors such as vascular endothelial growth factor (VEGF) released from tumor cells in hypoxia. It enhances solid tumor growth and provides an ability to establish metastasis at peripheral sites by tumor cell migration. Thymosin beta-4 (TB4) is an actin-sequestering protein to control cytoskeletal reorganization. Here, we investigated whether angiogenesis and tumor metastasis are dependent on hypoxia conditioning-induced TB4 expression in B16F10 melanoma cells. TB4 expression in B16F10 cells was increased by hypoxia conditioning in a time-dependent manner. In addition, we found an increase of angiogenesis and HIF-1α expression in TB4-transgenic (Tg) mice as compared to wildtype mice. When wound healing assay was used to assess in vitro tumor cell migration, hypoxia conditioning for 1 h enhanced B16F10 cell migration. When TB4 expression in B16F10 cells was inhibited by the infection with small hairpin (sh) RNA of TB4 cloned in lentiviral vector, tumor cell migration was retarded. In addition, hypoxia conditioning-induced tumor cell migration was reduced by the infection of lentiviral shRNA of TB4. HIF-1α stabilization and the expression of VEGF isoform 165 and 121 in hypoxia were also reduced by the infection of lentiviral shRNA of TB4 in B16F10 cells. We also found an increase of tumor growth and lung metastasis count in TB4-Tg mice as compared to wildtype mice. Collectively, hypoxia conditioning induced tumor cell migration by TB4 expression-dependent HIF-1α stabilization. It suggests that TB4 could be a hypoxia responsive regulator to control tumor cell migration in angiogenesis and tumor metastasis.

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Abbreviations

TB4:

Thymosin-beta-4

HIF-1α:

Hypoxia inducible transcription factor 1 alpha

VEGF:

Vascular endothelial growth factor

Tg:

Transgenic

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Acknowledgments

This work was supported by grants (#0920270) from National Cancer Control Program, (#A080076) of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare and National Nuclear R&D Program (#2010-0018545) through National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST), Korea.

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Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong Kwangjin-Gu, Seoul, 143-747, Korea

    Eun-Yi Moon, Yun-Sun Im & Yun-Kyoung Ryu

  2. Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, 139-709, Korea

    Joo-Hyun Kang

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  1. Eun-Yi Moon
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  2. Yun-Sun Im
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Correspondence to Eun-Yi Moon.

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Moon, EY., Im, YS., Ryu, YK. et al. Actin-sequestering protein, thymosin beta-4, is a novel hypoxia responsive regulator. Clin Exp Metastasis 27, 601–609 (2010). https://doi.org/10.1007/s10585-010-9350-z

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  • DOI: https://doi.org/10.1007/s10585-010-9350-z

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