Oliveira-Ferrer Leticia, Tilki Derya, Ziegeler Gudrun, Hauschild Jessica, Loges Sonja, Irmak Ster, Kilic Ergin, Huland Hartwig, Friedrich Martin, Ergün Süleyman
Institute of Anatomy I and Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Cancer Res. 2004 Dec 15;64(24):8932-8. doi: 10.1158/0008-5472.CAN-04-0505.
Here, we show that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in umbrella cells of bladder urothelium but is down-regulated in superficial bladder cancer, such as histologic tumor stage a (pTa) and transitional cell carcinoma in situ (pTis). Concurrently, CEACAM1 is up-regulated in the endothelia of adjacent angiogenic blood vessels. Mimicking the CEACAM1 down-regulation in the urothelium, CEACAM1 was silenced in bladder cancer cell lines 486p and RT4 using the small interfering RNA technique. CEACAM1 down-regulation was confirmed at the protein level by Western blot analyses. CEACAM1 silencing leads to a significant up-regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D in quantitative reverse transcription-PCR. Correspondingly, supernatants from the CEACAM1-overexpressing bladder cancer cell lines reduce, but those from CEACAM1 silencing induce endothelial tube formation and potentiate the morphogenetic effects of VEGF. These data suggest that the epithelial down-regulation of CEACAM1 induces angiogenesis via increased expression of VEGF-C and VEGF-D. Inversely, CEACAM1 is up-regulated in endothelial cells of angiogenic blood vessels. This in turn is involved in the switch from noninvasive and nonvascularized to invasive and vascularized bladder cancer. CEACAM1 appears to be a promising endothelial target for bladder cancer therapy.
在此，我们发现癌胚抗原相关细胞黏附分子1（CEACAM1）在膀胱尿路上皮伞细胞中表达，但在浅表性膀胱癌中下调，如组织学肿瘤分期a（pTa）和原位移行细胞癌（pTis）。同时，CEACAM1在相邻血管生成血管的内皮细胞中上调。利用小干扰RNA技术在膀胱癌细胞系486p和RT4中沉默CEACAM1，模拟尿路上皮中CEACAM1的下调。通过蛋白质印迹分析在蛋白质水平证实了CEACAM1的下调。在定量逆转录聚合酶链反应中，CEACAM1沉默导致血管内皮生长因子（VEGF）-C和VEGF-D显著上调。相应地，来自过表达CEACAM1的膀胱癌细胞系的上清液减少，但来自CEACAM1沉默细胞系的上清液诱导内皮管形成并增强VEGF的形态发生作用。这些数据表明，CEACAM1的上皮下调通过增加VEGF-C和VEGF-D的表达诱导血管生成。相反，CEACAM1在血管生成血管的内皮细胞中上调。这反过来又参与了从非侵袭性和无血管化到侵袭性和血管化膀胱癌的转变。CEACAM1似乎是膀胱癌治疗中一个有前景的内皮靶点。
