Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis.
Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis.
复制标题
DOI：
10.1186/1476-4598-8-11
复制
发表时间：
2009-02-28
期刊：
影响因子：
37.3
通讯作者：
Yen Y
中科院分区：
文献类型：
--
作者：
Zhang K;Hu S;Wu J;Chen L;Lu J;Wang X;Liu X;Zhou B;Yen Y
除了在核糖核苷酸还原中发挥重要作用外，核糖核苷酸还原酶(RNR)小亚基RRM2已被认为在判断肿瘤恶性程度中起着关键作用。RRM2的过表达显著增强了肿瘤的侵袭和转移潜能。血管生成与肿瘤的恶性程度密切相关，在肿瘤的生长和转移中起着至关重要的作用。研究RRM2是否影响肿瘤的血管生成潜能是非常重要的。我们检测了抗血管生成血栓反应蛋白-1(TSP-1)和促血管生成血管内皮生长因子(VEGF)在两个过表达RRM2的KB细胞：KB-M2-D和KB-HURS中的表达。我们发现在KB-M2-D和KB-HURS细胞中，TSP-1的表达均显著低于亲本KB和模拟转染组。同时，过表达RRM2的KB细胞表现出较高的VEGFmRNA和蛋白水平。相反，通过siRNA抑制RRM2的表达可显著增加KB和LNCaP细胞中TSP-1的表达，而在常氧和低氧条件下，这两种细胞的血管内皮生长因子的表达均显著降低。与KB-V相比，RRM2过表达对KB-M2-D的体外增殖无明显影响，但可显著促进KB-M2-D的皮下生长。与KB-V相比，KB-M2-D具有更强的血管生成能力，在体外，其对内皮细胞的趋化能力增强，在体内，通过生成更多的血管化的肿瘤移植瘤来证明。这些发现提示RRM2通过调节TSP-1和VEGF的表达而在肿瘤血管生成和生长中发挥积极作用。
In addition to its essential role in ribonucleotide reduction, ribonucleotide reductase (RNR) small subunit, RRM2, has been known to play a critical role in determining tumor malignancy. Overexpression of RRM2 significantly enhances the invasive and metastatic potential of tumor. Angiogenesis is critical to tumor malignancy; it plays an essential role in tumor growth and metastasis. It is important to investigate whether the angiogenic potential of tumor is affected by RRM2. We examined the expression of antiangiogenic thrombospondin-1 (TSP-1) and proangiogenic vascular endothelial growth factor (VEGF) in two RRM2-overexpressing KB cells: KB-M2-D and KB-HURs. We found that TSP-1 was significantly decreased in both KB-M2-D and KB-HURs cells compared to the parental KB and mock transfected KB-V. Simultaneously, RRM2-overexpressing KB cells showed increased production of VEGF mRNA and protein. In contrast, attenuating RRM2 expression via siRNA resulted in a significant increased TSP-1 expression in both KB and LNCaP cells; while the expression of VEGF by the two cells was significantly decreased under both normoxia and hypoxia. In comparison with KB-V, overexpression of RRM2 had no significant effect on proliferation in vitro, but it dramatically accelerated in vivo subcutaneous growth of KB-M2-D. KB-M2-D possessed more angiogenic potential than KB-V, as shown in vitro by its increased chemotaxis for endothelial cells and in vivo by the generation of more vascularized tumor xenografts. These findings suggest a positive role of RRM2 in tumor angiogenesis and growth through regulation of the expression of TSP-1 and VEGF.
登录
查看更多内容
DOI：
10.1073/pnas.171460498
发表时间：
2001-10-23
影响因子：
11.1
作者：
Rodríguez-Manzaneque, JC;Lane, TF;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
DOI：
10.1073/pnas.94.24.13181
发表时间：
1997-11-25
影响因子：
11.1
作者：
Fan, HZ;Huang, AP;Wright, JA
通讯作者：
Wright, JA
影响因子：
4.7
作者：
Gutierrez, LS;Suckow, M;Castellino, FJ
通讯作者：
Castellino, FJ
影响因子：
8.5
作者：
Graff, P;Seim, J;Pettersen, EO
通讯作者：
Pettersen, EO
影响因子：
3.4
作者：
Liu, Xiyong;Zhou, Bingsen;Yen, Yui
通讯作者：
Yen, Yui