Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions
Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions
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DOI：
10.1038/onc.2010.498
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发表时间：
2011-03-01
期刊：
影响因子：
8
通讯作者：
Chi, S. G.
中科院分区：
文献类型：
--
作者：
Chae, K. S.;Kang, M. J.;Chi, S. G.
转化生长因子（TGF）-β 1在前列腺肿瘤发生中具有双相功能，在早期阶段具有生长抑制作用，但在晚期阶段促进肿瘤血管生成和转移。我们在这里证明，肿瘤产生TGF-β 1诱导前列腺癌细胞中的血管内皮生长因子（VEGF），缺氧诱导因子（HIF）-1 α和HIF-2 α在非缺氧条件下TGF-β 1调节VEGF表达中具有相反的功能。VEGF对TGF-β 1的启动子反应通过HIF-2 α或siHIF-1 α的转染而上调，但通过HIF-1 α和siHIF-2 α而下调。HIF-1 α和HIF-2 α在mRNA和蛋白水平上均被TGF-β 1诱导，然而，它们的核转位受到TGF-β 1的不同调节，这表明其与它们的相反作用相关。TGF-β 1对VEGF的诱导作用是以Smad 3依赖的方式发生的，VEGF启动子中的Smad结合元件2（SBE 2，-992至-986）和缺氧反应元件（-975至-968）是启动子对TGF-β 1的反应所必需的。Smad 3与HIF-2 α在VEGF转录的TGF-β 1激活中协同作用，并且Smad 3与SBE 2位点的结合被HIF-2 α表达的敲低大大削弱。此外，VEGF启动子对TGF-β 1的反应通过Smad 3和HIF-2 α的共转染而协同升高，但通过HIF-1 α以剂量依赖性方式减弱。此外，发现TGF-β 1通过促进RNA稳定因子HuR的细胞质易位来增加VEGF转录物的稳定性。总的来说，我们的数据表明，肿瘤产生TGF-β 1诱导VEGF在转录和转录后水平通过多种途径，包括Smad 3，HIF-2 α和HuR。因此，这项研究表明，自分泌TGF-β 1的生产可能有助于肿瘤血管生成通过HIF-2 α信号在非缺氧条件下，提供了一个选择性的前列腺肿瘤细胞的生长优势。Oncogene（2011）30，1213-1228; doi：10.1038/onc.2010.498; 2010年11月8日在线发表
Transforming growth factor (TGF)-beta 1 has biphasic functions in prostate tumorigenesis, having a growth-inhibitory effect in the early stages, but in the late stages promoting tumor angiogenesis and metastasis. We demonstrate here that tumor-producing TGF-beta 1 induces vascular endothelial growth factor (VEGF) in prostate cancer cells, and hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha has opposite functions in TGF-beta 1 regulation of VEGF expression under non-hypoxic conditions. The promoter response of VEGF to TGF-beta 1 was upregulated by the transfection of HIF-2 alpha or siHIF-1 alpha but downregulated by HIF-1 alpha and siHIF-2 alpha. Both HIF-1 alpha and HIF-2 alpha were induced by TGF-beta 1 at mRNA and protein levels, however, their nuclear translocation was differentially regulated by TGF-beta 1, suggesting its association with their opposite effects. VEGF induction by TGF-beta 1 occurred in a Smad3-dependent manner, and the Smad-binding element 2 (SBE2, -992 to -986) and hypoxia response element (-975 to -968) in the VEGF promoter were required for the promoter response to TGF-beta 1. Smad3 cooperated with HIF-2 alpha in TGF-beta 1 activation of VEGF transcription and Smad3 binding to the SBE2 site was greatly impaired by knockdown of HIF-2 alpha expression. Moreover, the VEGF promoter response to TGF-beta 1 was synergistically elevated by co-transfection of Smad3 and HIF-2 alpha but attenuated by HIF-1 alpha in a dose-dependent manner. Additionally, TGF-beta 1 was found to increase the stability of VEGF transcript by facilitating the cytoplasmic translocation of a RNA-stabilizing factor HuR. Collectively, our data show that tumor-producing TGF-beta 1 induces VEGF at the both transcription and post-transcriptional levels through multiple routes including Smad3, HIF-2 alpha and HuR. This study thus suggests that autocrine TGF-beta 1 production may contribute to tumor angiogenesis via HIF-2 alpha signaling under non-hypoxic conditions, providing a selective growth advantage for prostate tumor cells. Oncogene (2011) 30, 1213-1228; doi:10.1038/onc.2010.498; published online 8 November 2010