Orphan nuclear receptor TR3/Nur77 differentially regulates the expression of integrins in angiogenesis

被引:16
|
作者
Ye, Taiyang [1 ,2 ,3 ]
Peng, Jin [1 ,2 ,4 ]
Liu, Xin [1 ,2 ,5 ]
Hou, Shiqiang [1 ,2 ,6 ]
Niu, Gengming [1 ,2 ,7 ]
Li, Yan [1 ,2 ,8 ]
Zeng, Huiyan [1 ,2 ]
Zhao, Dezheng [1 ,2 ]
机构
[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA
[2] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Dept Med, 99 Brookline Ave RN 270F, Boston, MA 02215 USA
[3] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Obstet & Gynecol, Shanghai 200127, Peoples R China
[4] Wuhan Univ, Radiotherapy & Med Oncol Dept, Zhongnan Hosp, Wuhan, Hubei, Peoples R China
[5] Capital Med Univ, Beijing Tradit Chinese Med Hosp, Beijing, Peoples R China
[6] Fudan Univ, Zhongshan Hosp, Dept Cardiol, Shanghai 200032, Peoples R China
[7] Fudan Univ, Huashan Hosp, Dept Gen Surg, Shanghai 200040, Peoples R China
[8] Shandong Univ, Dept Gastroenterol, Shandong Prov Hosp, Jinan 250021, Shandong, Peoples R China
关键词
TR3/Nur77; Angiogenesis; Integrin; Promoter; Proliferation; Migration; ANTI-VEGF THERAPY; ANTIANGIOGENIC THERAPY; TUMOR REFRACTORINESS; NGFI-B; CELLS; PERMEABILITY; RESISTANCE; PROTEIN; NUR77; NURR1;
D O I
10.1016/j.mvr.2018.10.011
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 (human homolog, Nur77, mouse homolog) is a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via down-regulating the expression of the junctional proteins and integrin beta 4. However, the molecular mechanism, by which TR3/Nur77 regulated angiogenesis, was still not completely understood. In this report by analyzing the integrin expression profile in endothelial cells, we found that the TR3/Nur77 expression highly increased the expression of integrins alpha 1 and beta 5, decreased the expression of integrins alpha 2 and beta 3, but had some or no effect on the expression of integrins alpha v, alpha 3, alpha 4, alpha 5, alpha 6,beta 1 and beta 7. In the angiogenic responses mediated by TR3/Nur77, integrin alpha 1 regulated endothelial cell proliferation and adhesion, but not migration. Integrin beta 5 shRNA inhibited cell migration, but increased proliferation and adhesion. Integrin alpha 2 regulated all of the endothelial cell proliferation, migration and adhesion. However, integrin beta 3 did not play any role in endothelial cell proliferation, migration and adhesion. TR3/Nur77 regulated the transcription of integrins alpha 1, alpha 2, beta 3 and beta 5, via various amino acid fragments within its transactivation domain and DNA binding domain. Furthermore, TR3/Nur77 regulated the integrin alpha 1 promoter activity by directly interacting with a novel DNA element within the integrin alpha 1 promoter. These studies furthered our understanding of the molecular mechanism by which TR3/Nur77 regulated angiogenesis, and supported our previous finding that TR3/Nur77 was an excellent therapeutic target for pathological angiogenesis. Therefore, targeting TR3/Nur77 inhibits several signaling pathways that are activated by various angiogenic factors.
引用
收藏
页码:22 / 33
页数:12
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