Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma.
Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma.
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发表时间：
2001-05
期刊：
影响因子：
11.2
通讯作者：
Q. Shi;X. Le;J. Abbruzzese;Zhihai Peng;C. Qian;Hong-wei Tang;Q. Xiong;Bailiang Wang;Xiang Chen Li-X
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文献类型：
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作者：
Q. Shi;X. Le;J. Abbruzzese;Zhihai Peng;C. Qian;Hong-wei Tang;Q. Xiong;Bailiang Wang;Xiang Chen Li-X
血管内皮生长因子（VEGF）是一种重要的血管生成分子，在包括胰腺癌在内的多种人类癌症的生长和转移中起重要作用。在这项研究中，我们探讨了血管内皮生长因子在人胰腺癌细胞的调节。在体外研究的人胰腺癌细胞系中，超过70%分泌组成性高水平的VEGF。高VEGF分泌细胞通常也表达升高的VEGF mRNA稳态水平。动力学分析表明，VEGF mRNA的稳态水平升高是由于增强VEGF基因转录和增加组成型VEGF启动子活性。VEGF启动子的缺失突变分析显示，从-109到-38 bp的区域是组成型VEGF启动子活性所必需的。进一步的缺失和点突变分析表明，个别或所有的推定的Sp1结合位点的突变减少或消除了组成型VEGF启动子的活性和废除的启动子在高和低VEGF表达细胞的差异活性。与组成型VEGF转录激活一致，在过表达VEGF的胰腺癌细胞系和胰腺癌组织标本中检测到高水平的组成型Sp1表达和活性。总的来说，我们的数据表明，组成性Sp1激活是必不可少的差异过度表达的VEGF，这反过来又起着重要的作用，在血管生成和人类胰腺癌的进展。
Vascular endothelial growth factor (VEGF) is a key angiogenic molecule that plays an important role in the growth and metastasis of many types of human cancer, including pancreatic adenocarcinoma. In this study, we explored the regulation of VEGF in human pancreatic cancer cells. Over 70% of the human pancreatic cancer cell lines studied in vitro secreted constitutively high levels of VEGF. High VEGF-secreting cells also generally expressed an elevated steady-state level of VEGF mRNA. Kinetic analysis revealed that the elevated steady-state level of VEGF mRNA was due to enhanced VEGF gene transcription and increased constitutive VEGF promoter activity. Deletive mutation analyses of the VEGF promoter revealed that the region from -109 to -38 bp was essential for constitutive VEGF promoter activity. Further deletion and point mutation analyses indicated that mutation of individual or all of the putative Sp1 binding sites reduced or eliminated the constitutive VEGF promoter activity and abrogated the differential activity of the promoter in high and low VEGF-expressing cells. Consistent with the constitutive VEGF transcription activation, a high level of constitutive Sp1 expression and activity was detected in pancreatic cancer cell lines and pancreatic cancer tissue specimens overexpressing VEGF. Collectively, our data demonstrated that constitutive Sp1 activation is essential for the differential overexpression of VEGF, which in turn plays an important role in the angiogenesis and progression of human pancreatic cancer.