Activator protein 2α inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells
Activator protein 2α inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells
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DOI：
10.1158/0008-5472.can-03-2751
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发表时间：
2004-01-15
期刊：
影响因子：
11.2
通讯作者：
Bar-Eli, M
中科院分区：
文献类型：
--
作者：
Ruiz, M;Pettaway, C;Bar-Eli, M
激活蛋白-2α(AP-2)是一种转录因子，调节哺乳动物细胞的增殖和分化。我们先前已经发现，虽然AP-2在正常前列腺上皮中高表达，但在高级别前列腺上皮内瘤变和前列腺癌中表达缺失，提示AP-2的缺失在前列腺癌的发生发展中起一定作用。我们证明，在前列腺癌细胞系LNCaP-LN3(AP-2阴性)中强制表达AP-2显著抑制了裸鼠的肿瘤发生率。为了确定可能对这种影响负责的基因，我们使用了微芯片表达阵列。我们发现几个已知与恶性肿瘤有关的基因被解除了调控，包括血管内皮生长因子(VEGF)基因。由于血管内皮生长因子在AP-2转基因细胞中下调了14.7倍，而且它是前列腺癌发生和发展的主要血管生成因子，我们选择检测AP-2-血管内皮生长因子的相互作用。我们的证据表明，AP-2通过与转录激活因子SP3竞争而在转录上抑制了血管内皮生长因子启动子。前列腺癌细胞中AP-2的缺失降低了AP-2/SP3的比例，激活了VEGF的表达。AP-2在前列腺癌中起肿瘤抑制基因的作用。阐明AP-2在前列腺上皮细胞中缺失所引起的分子事件对于理解和预防前列腺癌的发生具有重要意义。
Activator protein-2alpha (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells. We have shown previously that although AP-2 is expressed highly in normal prostatic epithelium, its expression is lost in high-grade prostatic intraepithelial neoplasia and prostate cancer, suggesting that loss of AP-2 plays a role in prostate cancer development. We demonstrate that forced AP-2 expression in the prostate cancer cell line LNCaP-LN3 (AP-2 negative) inhibited dramatically tumor incidence in nude mice. To identify the genes that might have been responsible for this effect, we used microchip expression array. We found several genes known to be involved in malignancy were deregulated, including the vascular endothelial growth factor (VEGF) gene. Because VEGF was down-regulated by 14.7-fold in the AP-2-transfected cells and because it is a major angiogenic factor in prostate cancer development and progression, we chose to examine the AP-2-VEGF interaction. Our evidence suggests that AP-2 repressed transcriptionally the VEGF promoter by competing with the transcriptional activator Sp3. Loss of AP-2 in prostate cancer cells reduced the AP-2:Sp3 ratio and activated VEGF expression. AP-2 acts as a tumor-suppressor gene in prostate cancer. Elucidating the molecular events resulting from loss of AP-2 in the prostate epithelium has implications for the understanding and prevention of the onset of prostate cancer.