Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-kappa B pathway

doi:10.1016/j.bbadis.2018.01.021

科研成果详情

题名	Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-kappa B pathway
作者	Jia, Mengqi 1; Guo, Yanxia 1; Zhu, Deyu 1; Zhang, Nianzhao 2; Li, Lin 3; Jiang, Jin 1; Dong, Yiwen 1; Xu, Qingqing 1; Zhang, Xiulei 1; Wang, Meijuan 1; Yu, Haina 1; Wang, Fang 4; Tian, Keli 1; Zhang, Jinsan5,6; Young, Charles Y.F.7; Lou, Hongxiang 3; Yuan, Huiqing 1
发表日期	2018-05
发表期刊	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	AGR2 Prostate cancer Invasion and metastasis VEGFA Angiogenesis
其他关键词	CANCER ; GROWTH ; CELL ; EXPRESSION ; INVASION ; REQUIRES
摘要	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.
资助项目	973 ProgramNational Basic Research Program of China [2013CB910900]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81273533, 81473238]; Program for Changjiang Scholars and Innovative Research Team in UniversityProgram for Changjiang Scholars & Innovative Research Team in University (PCSIRT) [IRT13028]; Shandong Scientific Technology Program [2015GSF118009]; Shandong Provincial Natural Science FoundationNatural Science Foundation of Shandong Province [ZR2014HM087, BS2015YY034]; National Undergraduate Training Program for Innovation and Entrepreneurship [201610422123]
出版者	ELSEVIER
出版地	AMSTERDAM
ISSN	0925-4439
EISSN	1879-260X
卷号	1864 期号:5 页码:1622-1633
DOI	10.1016/j.bbadis.2018.01.021
页数	12
WOS类目	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS记录号	WOS:000430883100008
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	29410027
SCOPUSEID	2-s2.0-85042687080
通讯作者地址	[Yuan, Huiqing]Department of Biochemistry and Molecular Biology,Shandong University School of Medicine,44 Wenhua Xi Road,Jinan,250012,China
Scopus学科分类	Molecular Medicine;Molecular Biology
引用统计	被引频次：24[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/10313
专题	药学院（分析测试中心）附属第一医院第一临床医学院（信息与工程学院）、附属第一医院_精准医学中心实验室
通讯作者	Yuan, Huiqing
作者单位	1.Department of Biochemistry and Molecular Biology,Shandong University School of Medicine,Jinan,China; 2.Department of Urology,Qilu Hospital of Shandong University,Jinan,China; 3.Department of Nature Product Chemistry,Key Laboratory of Chemical Biology of Ministry of Education,Shandong University School of Pharmaceutical Sciences,Jinan,China; 4.Center for Stem Cell and Regenerative Medicine,The Second Hospital of Shandong University,Jinan,China; 5.School of Pharmaceutical Sciences and Center for Precision Medicine,The First Affiliated Hospital,Wenzhou Medical University,China; 6.Institute of Life Sciences,Wenzhou University,Wenzhou,China; 7.Department of Urology,Mayo Clinic College of Medicine,Mayo Clinic,Rochester,United States
推荐引用方式 GB/T 7714	Jia, Mengqi,Guo, Yanxia,Zhu, Deyu,et al. Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-kappa B pathway[J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE,2018,1864(5):1622-1633.
APA	Jia, Mengqi., Guo, Yanxia., Zhu, Deyu., Zhang, Nianzhao., Li, Lin., ... & Yuan, Huiqing. (2018). Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-kappa B pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1864(5), 1622-1633.
MLA	Jia, Mengqi,et al."Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-kappa B pathway".BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1864.5(2018):1622-1633.