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Cold shock domain protein A represses angiogenesis and lymphangiogenesis via inhibition of serum response element

Oncogene volume 27, pages 1821–1833 (2008)Cite this article

Abstract

Dual-targeted therapy for antiangiogenesis and antilymphangiogenesis represents a potentially effective strategy for the treatment of various malignancies. Therefore, the goal of the present study was to identify genes that encode inhibitors of both angiogenesis and lymphangiogenesis. Using a cDNA library obtained from Lewis lung carcinoma (LL/2), a candidate gene was identified by the evaluation of growth inhibition in aortic and lymphatic endothelial cells (EC) as that coding for the mouse cold shock domain protein A (mCSDA). Overexpression of mCSDA significantly repressed cell proliferation and c-fos promoter activity in aortic, venous and lymphatic ECs. CSDA is a DNA-binding protein that binds to the hypoxia response element (HRE). Furthermore, of importance, we revealed that CSDA could directly bind to the serum response element (SRE) sequence, resulting in the inhibition of SRE activity, which may lead to growth inhibition in ECs. In an LL/2-inoculated mouse model, tumor growth was significantly repressed in an mCSDA-injected group. Histopathological analysis revealed that expression of blood and lymphatic EC markers was significantly decreased in mCSDA-injected groups. In conclusion, these data suggest that expression of CSDA can repress angiogenesis and lymphangiogenesis via direct binding to SRE in addition to HRE.

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Acknowledgements

This work was supported by the Northern Osaka (Saito) Biomedical Knowledge-Based Cluster Creation Project and the Mitsubishi Pharma Research Foundation. We thank Prof. Hiroshi Nojima of Osaka University for technical assistance and advice in making cDNA library and Dr Gregory J Goodall of the Hanson Centre for Cancer Research, Institute of Medicine and Veterinary Science for providing the hCSDA plasmid.

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Authors and Affiliations

  1. Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan

    Y Saito, H Nakagami, M Kurooka, Y Takami, Y Kikuchi, H Hayashi, T Nishikawa, K Tamai & Y Kaneda

  2. Department of Surgery, Asahikawa Medical University, Hokkaido, Japan

    Y Saito, N Azuma & T Sasajima

  3. Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan

    R Morishita

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Correspondence to Y Kaneda.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Saito, Y., Nakagami, H., Kurooka, M. et al. Cold shock domain protein A represses angiogenesis and lymphangiogenesis via inhibition of serum response element. Oncogene 27, 1821–1833 (2008). https://doi.org/10.1038/sj.onc.1210824

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  • DOI: https://doi.org/10.1038/sj.onc.1210824

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