Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3.
Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3.
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DOI：
10.3892/or.12.1.47
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发表时间：
2004-07
期刊：
影响因子：
4.2
通讯作者：
M. Saino;T. Maruyama;T. Sekiya;T. Kayama;Y. Murakami
中科院分区：
文献类型：
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作者：
M. Saino;T. Maruyama;T. Sekiya;T. Kayama;Y. Murakami
恶性胶质瘤，其中大多数显示血管内皮细胞生长因子（VEGF）表达水平升高，是众所周知的，他们的血管丰富。肿瘤细胞中VEGF的可能诱导剂之一是一氧化氮（NO），它由NO合酶合成，刺激肿瘤细胞中的可溶性鸟苷酸环化酶（GC）。在这里，我们报告，2 9人胶质瘤细胞系，CCF-STTG 1和U-87 MG，过度产生环GMP（cGMP），并表现出增加表达的可溶性GC 1，GUCY1A3和GUCY1B3的两个或任何一个亚基。反义GUCY1A3或GUCY1B3转染两种胶质瘤细胞后，cGMP含量和VEGF表达均明显降低。体外血管生成活性随后被抑制，这通过诱导HUVEC细胞生长来确定。此外，通过转染反义GUCY1A3或反义GUCY1B3，裸鼠中U-87 MG细胞的皮下肿瘤形成被显著抑制至体积小于0.05%，这伴随着血管指数显著降低至约10%。这些研究结果表明，cGMP是在胶质瘤细胞中VEGF表达的上游介质，并且可溶性鸟苷酸环化酶可能是用于控制人类恶性胶质瘤的子集中的新血管形成的靶分子。
Malignant gliomas, most of which show an elevated level of vascular endothelial cell growth factor (VEGF) expression, are well known for their hyper-vascularity. One of the possible inducers of VEGF in tumor cells is nitric oxide (NO), which is synthesized by NO synthase and stimulates soluble guanylate cyclase (GC) in tumor cells. Here, we report that 2 of 9 human glioma cell lines, CCF-STTG1 and U-87MG, overproduced cyclic GMP (cGMP) and showed increased expression of both or either subunits of soluble GC1, GUCY1A3 and GUCY1B3. Transfection of antisense GUCY1A3 or GUCY1B3 into these two glioma cell lines markedly reduced the content of cGMP and expression of VEGF. The angiogenic activity in vitro was subsequently inhibited, which was determined by induction of HUVEC cell growth. Furthermore, subcutaneous tumor formation by U-87MG cells in nude mice was dramatically suppressed to less than 0.05% in volume by transfection of either antisense GUCY1A3 or antisense GUCY1B3, which was accompanied by the significant decrease in vascular index to about 10%. These findings demonstrate that cGMP is an upstream mediator of VEGF expression in glioma cells and that soluble guanylate cyclases could be the target molecules for controlling neo-vascularization in a subset of human malignant gliomas.