Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen
Enhanced expression of vascular endothelial growth factor (VEGF) plays a critical role in the tumor progression potential induced by simian virus 40 large T antigen
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DOI：
10.1038/sj.onc.1205382
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发表时间：
2002-04-25
期刊：
影响因子：
8
通讯作者：
Procopio, A
中科院分区：
文献类型：
--
作者：
Catalano, A;Romano, M;Procopio, A
血管内皮生长因子是一种重要的血管生成因子，通过激活其酪氨酸激酶受体，如Flt-1和Flk-1/KDR，调节细胞的增殖、分化和凋亡。携带野生型P53的人恶性间皮瘤细胞(HMC)表达血管内皮生长因子(VEGF)，并表现出明显的促细胞生长作用。在这里，我们证明了猴病毒(SV)40、大肿瘤抗原(TAG)和小肿瘤抗原(TAG)的早期转化蛋白。与间皮瘤相关，通过诱导血管内皮生长因子表达促进HNIC的增殖。SV40-Tag的表达可显著提高几种HNIC细胞中血管内皮生长因子的蛋白和mRNA水平。这种作用可被蛋白质合成抑制剂放线菌亚胺抑制。通过表达可溶性FIT-1使血管内皮生长因子信号转导通路失活，可抑制SV40早期基因诱导的Flk-1/KDR活化和HNIC增殖。用SV40突变体进行的实验表明，SV40-Tag而不是-Tag参与了血管内皮生长因子启动子的激活。而SV40-Tag的伴随表达增强了Tag的功能。此外，SV40-Tag在野生型p53的结肠癌细胞系CCL-233中持续诱导血管内皮生长因子的表达，而在缺乏功能性P53的结肠癌细胞系CCL-238中不能。这些数据表明，SV40转化蛋白对血管内皮生长因子的调节可能是SV40信号通路中与肿瘤进展相关的一个关键事件。
Vascular endothelial growth factor (VEGF), an important angiogenic factor, regulates cell proliferation, differentiation, and apoptosis through activation of its tyrosine-kinase receptors, such as Flt-1 and Flk-1/Kdr. Human malignant mesothelioma cells (HMC), which have wild-type p53, express VEGF and exhibit cell growth increased by VEGF. Here, we demonstrate that early transforming proteins of simian virus (SV) 40, large tumor antigen (Tag) and small tumor antigen (tag). which have been associated with mesotheliomas, enhanced HNIC proliferation by inducing VEGF expression. SV40-Tag expression potently increased VEGF protein and mRNA levels in several HNIC lines. This effect was suppressed by the protein synthesis inhibitor, cycloheximide. Inactivation of the VEGF signal transduction pathway by expression of soluble form of FIt-1 inhibited Flk-1/Kdr activation and HNIC proliferation induced by SV40 early genes. Experiments with SV40 mutants revealed that SV40-Tag, but not -tag, is involved in the VEGF promoter activation. However, concomitant expression of SV40-tag enhanced Tag function. In addition, SV40-Tag expression sustained VEGF induction in colon carcinoma cell line (CCL)-233, which have wild-type p53, but not in CCL-238, which lack functional p53. These data indicate that VEGF regulation by SV40 transforming proteins can represent a key event in SV40 signaling relevant for tumor progression.