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Published on: February 16, 2018
Cold shock domain protein A represses angiogenesis and lymphangiogenesis via inhibition of serum response element
Y Saito1, H Nakagami, M Kurooka
1Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
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.
Insights
Mouse cold shock domain protein A (mCSDA) inhibits both blood vessel and lymphatic vessel growth. This dual-targeted therapy approach shows promise for treating cancers by repressing tumor angiogenesis and lymphangiogenesis.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Dual-targeted therapy inhibiting angiogenesis and lymphangiogenesis is a promising strategy for cancer treatment.
- Identifying genes that inhibit both processes is crucial for developing novel anti-cancer therapies.
Purpose of the Study:
- To identify genes encoding inhibitors of both angiogenesis and lymphangiogenesis.
- To investigate the role of mouse cold shock domain protein A (mCSDA) in regulating endothelial cell proliferation and tumor growth.
Main Methods:
- Utilized a cDNA library from Lewis lung carcinoma (LL/2) to identify candidate genes.
- Evaluated growth inhibition in aortic and lymphatic endothelial cells (ECs) upon mCSDA overexpression.
- Assessed tumor growth and EC marker expression in an LL/2 mouse model following mCSDA injection.
Main Results:
- mCSDA overexpression significantly repressed proliferation and c-fos promoter activity in various ECs.
- CSDA directly binds to the hypoxia response element (HRE) and serum response element (SRE), inhibiting their activity.
- mCSDA injection significantly repressed tumor growth and decreased blood and lymphatic EC markers in vivo.
Conclusions:
- CSDA acts as a dual inhibitor of angiogenesis and lymphangiogenesis.
- mCSDA demonstrates potential as a therapeutic agent for repressing tumor growth by targeting both blood and lymphatic vessel formation.
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