Cold shock domain protein A represses angiogenesis and lymphangiogenesis via inhibition of serum response element
Cold shock domain protein A represses angiogenesis and lymphangiogenesis via inhibition of serum response element
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DOI：
10.1038/sj.onc.1210824
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发表时间：
2008-03
期刊：
影响因子：
8
通讯作者：
Y. Saito;H. Nakagami;M. Kurooka;Y. Takami;Y. Kikuchi;H. Hayashi;T. Nishikawa;K. Tamai;R. Morishita;N. Azuma;T. Sasajima;Y. Kaneda
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文献类型：
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作者：
Y. Saito;H. Nakagami;M. Kurooka;Y. Takami;Y. Kikuchi;H. Hayashi;T. Nishikawa;K. Tamai;R. Morishita;N. Azuma;T. Sasajima;Y. Kaneda
抗血管生成和抗淋巴管生成的双靶向治疗代表了治疗各种恶性肿瘤的潜在有效策略。因此，本研究的目的是确定基因编码抑制血管生成和淋巴管生成。利用从刘易斯肺癌（LL/2）中获得的cDNA文库，通过评估主动脉和淋巴管内皮细胞（EC）的生长抑制来鉴定候选基因，其为编码小鼠冷休克结构域蛋白A（mCSDA）的基因。在主动脉、静脉和淋巴管内皮细胞中，过表达mCSDA显著抑制细胞增殖和c-fos启动子活性。CSDA是一种DNA结合蛋白，与缺氧反应元件（HRE）结合。此外，重要的是，我们发现，CSDA可以直接结合到血清反应元件（SRE）序列，导致SRE活性的抑制，这可能导致EC的生长抑制。在LL/2接种的小鼠模型中，mCSDA注射组的肿瘤生长受到显著抑制。组织学分析显示，在注射mCSDA的组中，血液和淋巴EC标志物的表达显著降低。总之，这些数据表明，CSDA的表达可以抑制血管生成和淋巴管生成通过直接结合到SRE除了HRE。
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.