Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway
Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway
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AGR2 的促转移活性通过与 VEGFA 的直接相互作用和 NF-κ B 通路的激活来中断血管生成目标贝伐珠单抗的效率
DOI：
10.1016/j.bbadis.2018.01.021
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发表时间：
2018-05-01
影响因子：
6.2
通讯作者：
Yuan, Huiqing
中科院分区：
文献类型：
--
作者：
Jia, Mengqi;Guo, Yanxia;Yuan, Huiqing
前梯度2（AGR 2），内质网（ER）驻留蛋白二硫键异构酶（PDI），与癌症的发展和恶性进展。在这里，我们表明，高水平的AGR 2促进前列腺癌（PCa）小鼠模型的侵袭性表型，该模型通过患者来源的异种移植物或手术前列腺内植入PCa细胞开发，与肿瘤组织中血管网络的富集相关。血管生成标志物VEGFR 2和CD 34以及侵袭性标志物Vimentin主要在转移性肝组织中染色。分泌的AGR 2被定义为增强VEGFR 2活性，如纯化的重组人AGR 2（rhAGR 2）与rhVEGFA通过形成二硫键的物理相互作用所证明的。rhAGR 2中突变或缺失的硫氧还蛋白基序也不能与rhVEGFA结合，导致血管形成的显著消除，但部分影响侵袭过程，暗示AGR 2赋予转移需要替代机制。胞浆AGR 2促进细胞转移归因于其对p65蛋白的稳定作用，其随后激活NF-κ B并促进上皮向间充质转化（EMT）。重要的是，GSH和卡博替尼，而不是贝伐单抗，在体外和体内有效地阻断了rhAGR 2的促血管生成作用，提供了证据表明分泌的AGR 2作为预测性生物标志物，用于基于其在循环系统中的水平选择靶向血管生成的治疗药物。
Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient-derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues. Secreted AGR2 was defined to enhance VEGFR2 activity as evidenced by physical interaction of purified recombinant human AGR2 (rhAGR2) with rhVEGFA through the formation of a disulfide bond. Mutant or deleted thioredoxin motif in rhAGR2 was also unable to bind to rhVEGFA that led to the significant abolishment in the vessel formation, but partially affecting the aggressive process, implicating alternative mechanisms are required for AGR2-conferring metastasis. Cytosolic AGR2 contributed to cell metastasis ascribed to its stabilizing effect on p65 protein, which subsequently activated the NF-kappa B and facilitated epithelial to mesenchymal transition (EMT). Importantly, GSH and cabozantinib, but not bevacizumab, effectively blocked the pro-angiogenic effect of rhAGR2 in vitro and in vivo, providing evidence that secreted AGR2 acts as a predictive biomarker for selection of angiogenesis-targeting therapeutic drugs based on its levels in the circular system.