Peroxiredoxin 1 stimulates endothelial cell expression of VEGF via TLR4 dependent activation of HIF-1α.
Peroxiredoxin 1 stimulates endothelial cell expression of VEGF via TLR4 dependent activation of HIF-1α.
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DOI：
10.1371/journal.pone.0050394
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gollnick SO
中科院分区：
文献类型：
--
作者：
Riddell JR;Maier P;Sass SN;Moser MT;Foster BA;Gollnick SO
慢性炎症导致形成促肿瘤的微环境，通过增强肿瘤血管生成促进肿瘤的发展、生长和分化。前列腺癌(CAP)的风险和预后与许多炎症和血管生成介质呈负相关，包括Toll样受体(TLRs)、核因子-κB和血管内皮生长因子。过氧化还蛋白1(PRX1)是一种TLR4的内源性配体，由帽细胞分泌，促进炎症反应。CAP细胞对PRX1的抑制导致血管内皮生长因子表达减少，肿瘤血管减少，肿瘤生长受阻。本研究旨在探讨PRX1在常氧条件下调节血管内皮细胞生长因子表达的机制。我们的结果表明，重组PRX1与小鼠血管内皮细胞孵育后，血管内皮生长因子的表达增加，这依赖于TLR4，需要缺氧诱导因子-1(HIF-1)与血管内皮生长因子启动子相互作用。血管内皮生长因子的诱导也依赖于核因子-κB，但是，核因子-κB与血管内皮生长因子启动子的相互作用不是诱导血管内皮生长因子表达所必需的，提示核因子-κB是间接作用于诱导血管内皮生长因子的表达。结果显示，PrX1刺激增加了NF-κB与HIF-1α启动子的相互作用，导致启动子活性增强和HIF-1α表达水平增加，并增强了HIF-1活性，从而导致血管内皮生长因子的表达。Prx1诱导的HIF-1也促进了NF-κB的活性，这表明存在一个正反馈环，有可能使Prx1诱导的血管生成永久化。值得注意的是，抑制PRX1在CAP中的表达伴随着HIF-1α表达的降低。本研究和我们先前研究的综合结果表明，PRX1与TLR4的相互作用可能通过慢性激活肿瘤血管生成来促进CAP生长。
Chronic inflammation leads to the formation of a pro-tumorigenic microenvironment that can promote tumor development, growth and differentiation through augmentation of tumor angiogenesis. Prostate cancer (CaP) risk and prognosis are adversely correlated with a number of inflammatory and angiogenic mediators, including Toll-like receptors (TLRs), NF-κB and vascular endothelial growth factor (VEGF). Peroxiredoxin 1 (Prx1) was recently identified as an endogenous ligand for TLR4 that is secreted from CaP cells and promotes inflammation. Inhibition of Prx1 by CaP cells resulted in reduced expression of VEGF, diminished tumor vasculature and retarded tumor growth. The mechanism by which Prx1 regulates VEGF expression in normoxic conditions was investigated in the current study. Our results show that incubation of mouse vascular endothelial cells with recombinant Prx1 caused increases in VEGF expression that was dependent upon TLR4 and required hypoxia inducible factor-1 (HIF-1) interaction with the VEGF promoter. The induction of VEGF was also dependent upon NF-κB; however, NF-κB interaction with the VEGF promoter was not required for Prx1 induction of VEGF suggesting that NF-κB was acting indirectly to induce VEGF expression. The results presented here show that Prx1 stimulation increased NF-κB interaction with the HIF-1α promoter, leading to enhanced promoter activity and increases in HIF-1α mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. Prx1 induced HIF-1 also promoted NF-κB activity, suggesting the presence of a positive feedback loop that has the potential to perpetuate Prx1 induction of angiogenesis. Strikingly, inhibition of Prx1 expression in CaP was accompanied with reduced expression of HIF-1α. The combined findings of the current study and our previous study suggest that Prx1 interaction with TLR4 promotes CaP growth potentially through chronic activation of tumor angiogenesis.
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DOI：
10.1016/j.bbrc.2006.04.073
发表时间：
2006-06-23
影响因子：
3.1
作者：
Chang, Jong Wook;Lee, Seung Hee;Yoo, Yung Joon
通讯作者：
Yoo, Yung Joon
影响因子：
4.8
作者：
Godoy, Alejandro;Watts, Anica;Smith, Gary J.
通讯作者：
Smith, Gary J.
影响因子：
6.4
作者：
An, HZ;Yu, YH;Cao, XT
通讯作者：
Cao, XT
影响因子：
4.4
作者：
Arrighi, JF;Rebsamen, M;Hauser, C
通讯作者：
Hauser, C
DOI：
10.1007/bf02674280
发表时间：
1997-09-01
期刊：
SOMATIC CELL AND MOLECULAR GENETICS
影响因子：
--
作者：
Kandel, ES;Chang, BD;Roninson, IB
通讯作者：
Roninson, IB