Department of Vascular Biology, Graduate School of Dental Medicine, N13 W7, Kita-ku, Sapporo 060-8586, Japan.
Br J Cancer. 2011 Mar 1;104(5):819-29. doi: 10.1038/bjc.2011.20. Epub 2011 Feb 1.
Tumour stromal cells differ from its normal counterpart. We have shown that tumour endothelial cells (TECs) isolated from tumour tissues are also abnormal. Furthermore, we found that mRNAs of vascular endothelial growth factor-A (VEGF-A) and cyclooxygenase-2 (COX-2) were upregulated in TECs. Vascular endothelial growth factor-A and COX-2 are angiogenic factors and their mRNAs contain an AU-rich element (ARE). AU-rich element-containing mRNAs are reportedly stabilised by Hu antigen R (HuR), which is exported to the cytoplasm.
Normal endothelial cell (NEC) and two types of TECs were isolated. We evaluated the correlation of HuR and accumulation of VEGF-A and COX-2 mRNAs in TECs and effects of HuR on biological phenotypes of TECs.
The HuR protein was accumulated in the cytoplasm of TECs, but not in NECs. Vascular endothelial growth factor-A and COX-2 mRNA levels decreased due to HuR knockdown and it was shown that these ARE-mRNA were bound to HuR in TECs. Furthermore, HuR knockdown inhibited cell survival, random motility, tube formation, and Akt phosphorylation in TECs.
Hu antigen R is associated with the upregulation of VEGF-A and COX-2 mRNA in TECs, and has an important role in keeping an angiogenic switch on, through activating angiogenic phenotype in tumour endothelium.
肿瘤基质细胞与正常组织不同。我们已经证明,从肿瘤组织中分离出的肿瘤内皮细胞(TEC)也是异常的。此外,我们发现 TEC 中血管内皮生长因子 A(VEGF-A)和环氧化酶-2(COX-2)的 mRNA 上调。VEGF-A 和 COX-2 是血管生成因子,其 mRNA 含有富含 AU 的元件(ARE)。据报道,含有 AU 丰富元件的 mRNA 被 Hu 抗原 R(HuR)稳定,HuR 被输出到细胞质中。
分离正常内皮细胞(NEC)和两种类型的 TEC。我们评估了 HuR 与 TEC 中 VEGF-A 和 COX-2 mRNA 积累的相关性,以及 HuR 对 TEC 生物学表型的影响。
HuR 蛋白在 TEC 的细胞质中积累,但在 NEC 中没有。由于 HuR 敲低,VEGF-A 和 COX-2 mRNA 水平下降,表明这些 ARE-mRNA 在 TEC 中与 HuR 结合。此外,HuR 敲低抑制了 TEC 中的细胞存活、随机迁移、管形成和 Akt 磷酸化。
Hu 抗原 R 与 TEC 中 VEGF-A 和 COX-2 mRNA 的上调有关,通过激活肿瘤内皮中的血管生成表型,在维持血管生成开关方面发挥重要作用。