Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF)
Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF)
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DOI：
10.1093/carcin/bgi128
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发表时间：
2005-10-01
期刊：
影响因子：
4.7
通讯作者：
Wong, YC
中科院分区：
文献类型：
--
作者：
Ling, MT;Lau, TCM;Wong, YC
雄激素非依赖性转移性前列腺癌是男性癌症相关死亡的主要原因。其中一个原因是对导致前列腺癌转移进展的分子机制缺乏了解。在这项研究中，我们已经证明，Id-1（分化/DNA合成抑制剂），螺旋-环-螺旋家族蛋白质的成员，过表达是通过激活血管内皮生长因子（VEGF）在前列腺癌细胞中促进血管生成的关键因素。使用异位转染Id-1基因的前列腺癌细胞，我们发现Id-1的上调通过激活VEGF基因转录诱导VEGF分泌。然而，下调Id-1导致VEGF分泌及其基因启动子活性的抑制。Id-1和VEGF之间的关联也通过免疫组织化学染色在人异种移植物上得到证实。此外，由表达Id-1的细胞产生的生长培养基能够以与重组人VEGF相似的程度促进人脐静脉内皮细胞（HUVEC）中的形态学变化以及毛细血管形成。此外，通过用Flk-1抑制剂SU 1498或VEGF中和抗体处理来抑制VEGF功能导致对HUVEC的血管生成作用逆转。我们的研究结果表明，Id-1在前列腺癌细胞中的过表达可能提供了一个自分泌信号，通过激活VEGF促进血管生成。由于在许多类型的晚期人类癌症中已经报道了Id-1的增加，我们的研究结果表明，Id-1的下调可能是通过抑制血管生成来抑制转移性癌症生长的新靶点。
Androgen-independent metastatic prostate cancer is the main cause of cancer related death in men. One of the reasons for this is the lack of understanding of the molecular mechanisms leading to the metastatic progression of prostate cancer. In this study, we have demonstrated that overexpression of Id-1 (inhibitor of differentiation/DNA synthesis), a member of the helix-loop-helix family proteins, is a key factor in promoting angiogenesis through activation of the vascular endothelial growth factor (VEGF) in prostate cancer cells. Using prostate cancer cells ectopically transfected with the Id-1 gene, we found that upregulation of Id-1 induced VEGF secretion through activation of the VEGF gene transcription. Downregulation of Id-1, however, led to the suppression of VEGF secretion and its gene promoter activity. The association between Id-1 and VEGF was also confirmed on human xenografts by immunohistochemical staining. In addition, the growth medium generated by the Id-1 expressing cells was able to promote morphological changes as well as capillary tube formation in human umbilical vein endothelial cells (HUVECs) at similar degrees to the recombinant human VEGF. Furthermore, inhibition of VEGF function by the treatment with an Flk-1 inhibitor, SU1498, or with the VEGF neutralizing antibody resulted in the reverse of the angiogenic effect on HUVECs. Our results suggest that overexpression of Id-1 in prostate cancer cells may provide an autocrine signal to promote angiogenesis through the activation of VEGF. Since increased Id-1 has been reported in many types of advanced human cancers, our results indicate that downregulation of Id-1 may be a novel target to inhibit the growth of metastatic cancers through the suppression of angiogenesis.